Fused heterocyclic compounds as ion channel modulators

ABSTRACT

The present invention relates to sodium channel inhibitors of Formula I: 
                         
in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7  are as defined above, and to their use in the treatment of various disease states, including cardiovascular diseases and diabetes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 13/706,786, filed Dec. 6, 2012, which is a continuation of U.S.patent application Ser. No. 12/607,823, filed Oct. 28, 2009, nowabandoned, which claims priority to U.S. Provisional Patent ApplicationSer. No. 61/161,011, filed Mar. 17, 2009 and U.S. Provisional PatentApplication Ser. No. 61/109,788, filed Oct. 30, 2008, the entireties ofeach of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel compounds and to their use in thetreatment of various disease states, including cardiovascular diseasesand diabetes. The invention also relates to methods for theirpreparation, and to pharmaceutical compositions containing suchcompounds.

BACKGROUND

The late sodium current (I_(NaL)) is a sustained component of the fastNa⁺ current of cardiac myocytes and neurons. Many common neurologicaland cardiac conditions are associated with abnormal (I_(NaL))enhancement, which contributes to the pathogenisis of both electricaland contactile dysfunction in mammals. See, for example, Pathophysiologyand Pharmacology of the Cardiac “Late Sodium Current”, Pharmacology andTherapeutics 119 (2008) 326-339. Accordingly, pharmaceutical compoundsthat selectively inhibit (I_(NaL)) in mammals are useful in treatingsuch disease states.

One example of a selective inhibitor of (I_(NaL)) is RANEXA®, a compoundapproved by the FDA for the treatment of chronic stable angina pectoris.RANEXA® has also been shown to be useful for the treatment of a varietyof cardiovascular diseases, including ischemia, reperfusion injury,arrhythmia and unstable angina, and also for the treatment of diabetes.It would be desirable to provide novel compounds that selectivelyinhibit (I_(NaL)) in mammals, and that have a similar spectrum ofactivity as RANEXA®, but with a lower potential for blocking thepotassium hERG channel.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel compounds of Formula(I) that function as late sodium channel blockers:

wherein:

-   R¹ is hydrogen or alkyl of 1-6 carbon atoms optionally substituted    by 1, 2 or 3 groups chosen from hydroxyl, alkoxy, halo, —C(O)R,    aryl, cycloalkyl, heterocyclyl, and heteroaryl, wherein said aryl,    cycloalkyl, heterocyclyl, or heteroaryl groups are optionally    substituted by one, two, or three groups independently chosen from    halo, hydroxyl, alkyl, —C(O)R, haloalkyl, alkoxy, aryl, or    cycloalkyl; in which R is hydroxy, alkoxy, or —NH₂,-   R² and R³ are each independently hydrogen, halo, alkoxy of 1-6    carbon atoms, optionally substituted alkyl of 1-6 carbon atoms,    —CF₃, —O—CF₃, or —CN, or-   R² and R³, taken together with the carbon to which they are both    attached form an optionally substituted cycloalkyl;-   R⁴ is phenyl optionally substituted by 1, 2, or 3 substituents    independently selected from the group consisting of alkyl of 1-6    carbon atoms, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo,    —NO₂, —CF₃, —O—CF₃, —CN, —O—R⁸, —S—R⁸, —N(R⁸)(R⁹), —S(═O)—R⁸,    —S(═O)₂R⁸, —S(═O)₂—N(R⁸)(R⁹), —S(═O)₂—O—R⁸, —N(R⁸)—C(O)—R⁹,    —N(R⁸)—C(O)—O—R⁹, —N(R⁸)—C(O)—N(R⁸)(R⁹), —C(O)—R⁸, —C(O)—O—R⁸,    —C(O)—N(R⁸)(R⁹), and —N(R⁸)—S(═O)₂—R⁹, wherein each said alkyl,    cycloalkyl, aryl, heteroaryl, and heterocyclyl is further optionally    substituted with halo, —NO₂, —CF₃, —O—CF₃, —N(R⁸)(R⁹), —C(O)—R⁸,    —C(O)—O—R⁸, —C(O)—N(R⁸)(R⁹), —CN, or —O—R⁸, in which R⁸ and R⁹ are    independently chosen from the group consisting of hydrogen, alkyl of    1-6 carbon atoms, heterocyclyl, aryl, and heteroaryl, wherein the    alkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted    with one, two, or three substituents independently selected from    halo, alkyl, mono- or dialkylamino, alkyl or aryl;-   R⁵ and R⁶ are each independently hydrogen, halo, alkoxy, optionally    substituted alkyl of 1-6 carbon atoms, —CF₃, —O—CF₃, or —CN, or-   R⁵ and R⁶, taken together with the carbon to which they are both    attached form an optionally substituted cycloalkyl;-   R⁷ is hydrogen, halo, cyano, or alkyl of 1-6 carbon atoms optionally    substituted by hydroxyl, alkoxy, halo, or —C(O)R,-   X¹ and X² are independently —N═ or —C(R¹⁰)═, wherein R¹⁰ is selected    from hydrogen, halo, hydroxyl, alkyl of 1-6 carbon atoms, alkoxy of    1-6 carbon atoms, —CF₃, —O—CF₃, —CN, or —N(R⁸)(R⁹);    and the pharmaceutically acceptable salts, esters, prodrugs, or    solvates thereof.

One embodiment of the invention includes compounds of Formula (I) inwhich X^(I) and X² are both —C(R¹⁰)═, particularly where R¹⁰ ishydrogen. Within this group are included compounds of Formula (I) inwhich R² and R³ are hydrogen or lower alkyl of 1-6 carbon atoms, and R⁵and R⁶ are hydrogen. Within this group is a subgroup of compounds ofFormula (I) in which R¹ is hydrogen or alkyl of 1-6 carbon atomsoptionally substituted by hydroxy, —C(O)R, trifluoromethyl, alkoxy of1-6 carbon atoms, or phenyl optionally substituted by —C(O)R.

Within this subgroup are compounds of Formula (I) in which R⁷ ishydrogen and R⁴ is phenyl optionally substituted by 1, 2, or 3substituents independently selected from the group consisting ofhydrogen, alkyl, hydroxyl, alkoxy, cyano, —C(O)NH₂, halo, or alkylsubstituted by 1, 2, 3, 4, 5 or 6 halo atoms, particularly fluoro.

In another embodiment, R¹ is hydrogen, alkyl of 1-6 carbon atomsoptionally substituted by 1, 2 or 3 groups chosen from —C(O)R, halo,hydroxy, heteroaryl substituted by optionally substituted phenyl, orphenyl optionally substituted by —C(O)R, and R² is methoxy, particularlywhere R⁴ is 6-(4-chlorophenyl) or 6-(4-trifluoromethylphenyl).

In another embodiment, R¹ is hydrogen or —C(O)R, where R is hydroxy,alkoxy of 1-6 carbon atoms, or —NH₂.

One embodiment provides a method of using the compounds of Formula (I)in the treatment of a disease or condition in a mammal that is amenableto treatment by a late sodium channel blocker. The compounds of theinvention and their therapeutically acceptable salts, esters, tautomericforms are of use as medicaments for the treatment of certain diseases,such as, cardiovascular diseases such as atrial and ventriculararrhythmias, heart failure (including congestive heart failure,diastolic heart failure, systolic heart failure, acute heart failure),Prinzmetal's (variant) angina, stable and unstable angina, exerciseinduced angina, congestive heart disease, ischemia, recurrent ischemia,reperfusion injury, myocardial infarction, acute coronary syndrome,peripheral arterial disease, and intermittent claudication. Suchdiseases may also include diabetes, and conditions related to diabetes,e.g. diabetic peripheral neuropathy. Such diseases may also includeconditions affecting the neuromuscular system resulting in pain,seizures, epilepsy, or paralysis. Such diseases may also includecerebrovascular disorders, such as stroke.

In another embodiment the invention provides pharmaceutical formulationscomprising a therapeutically effective amount of a compound of theinvention (e.g. a compound of Formula (I)) and at least onepharmaceutically acceptable excipient.

At present, the preferred compounds of the invention include, but arenot limited to:

6-(3-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one;

4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzamide;

6-(4-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one;

6-phenyl-3,4-dihydroquinolin-2(1H)-one;

4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile;

3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzamide;

6-(2-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one;

6-(3-acetylphenyl)-3,4-dihydroquinolin-2(1H)-one;

6-(3-fluorophenyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one;

6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;

6-[4-chloro-3-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;

6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one;

2-fluoro-5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile;

6-[3-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;

ethyl[6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;

1-(2-hydroxyethyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;

ethyl[6-(3,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;

6-(3,4-difluorophenyl)-1-(2-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one;

6-(2,4-difluorophenyl)-1-(2-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one;

ethyl {2-oxo-6-[3-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;

{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid;

ethyl{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;

{2-oxo-6-[3-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}aceticacid;

1-{[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one;

6-(2,4-difluorophenyl)-1-(2-methoxyethyl)-3,4-dihydroquinolin-2(1H)-one;

6-(2,4-difluorophenyl)-1-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-2(1H)-one;

6-(2,4-difluorophenyl)-1-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3,4-dihydroquinolin-2(1H)-one;

tert-butyl {2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;

tert-butyl[6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;

1-(2-hydroxyethyl)-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;

2-{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetamide;

1-[2-(morpholin-4-yl)-2-oxoethyl]-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;

tert-butyl[6-(4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;

[6-(4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1 (2H)-yl]acetic acid;

{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetonitrile;

1-(2-methoxyethyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;

6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;

tert-butyl {2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;

{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}aceticacid;

sodium{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;

tert-butyl[6-(3-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;

1-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl]-6-(4-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one;

1-(2-hydroxypropyl)-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;

6-(4-chlorophenyl)-3,4-dihydroquinolin-2(1H)-one;

1-(pyridin-3-ylmethyl)-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;

6-(4-phenoxyphenyl)-3,4-dihydroquinolin-2(1H)-one;

1-[(5-methylisoxazol-3-yl)methyl]-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;

tert-butyl[6-(4-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;

tert-butyl[2-oxo-6-(4-phenoxyphenyl)-3,4-dihydroquinolin-1(2H)-yl]acetate;

tert-butyl{6-[4-chloro-3-(trifluoromethyl)phenyl]-2-oxo-3,4-dihydroquinolin-1(2H)-yl}acetate;

[6-(4-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid;

[6-(3,4-dichlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid;

[2-oxo-6-(4-phenoxyphenyl)-3,4-dihydroquinolin-1 (2H)-yl]acetic acid;

3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile;

ethyl{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;

2-[6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetamide;

2-{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetamide;

2-{6-[4-chloro-3-(trifluoromethyl)phenyl]-2-oxo-3,4-dihydroquinolin-1(2H)-yl}acetamide;

[6-(4-chloro-3-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]aceticacid;

6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one;

8-bromo-6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one;

{7-methoxy-2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid;

[6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl]aceticacid;

[6,8-bis(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl]aceticacid;

4,4-dimethyl-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;

{4,4-dimethyl-2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}aceticacid;

[6-(3-chloro-4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]aceticacid;

[6-(3-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid;

4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoic acid;

methyl4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate;

6-(3-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one;

2-(6-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)aceticacid;

tert-butyl2-(6-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate;

ethyl3-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate;

6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one;

7-methoxy-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;

6,8-bis(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one;

6-[3-(morpholin-4-ylcarbonyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;

tert-butyl2-(6-(3,4-dichlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate;

tert-butyl-2-(7-methoxy-2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate;

1-benzyl-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one; and

2-(2-oxo-6-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinolin-1(2H)-yl)aceticacid.

DETAILED DESCRIPTION OF THE INVENTION

Definitions and General Parameters

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise.

The term “alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having from 1 to 20 carbon atoms. This termis exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.

The term “substituted alkyl” refers to:

-   -   1) an alkyl group as defined above, having 1, 2, 3, 4 or 5        substituents, (typically 1, 2, or 3 substituents) selected from        the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl,        cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,        alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto,        thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,        heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,        aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,        heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl,        —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and        —SO₂-heteroaryl. Unless otherwise constrained by the definition,        all substituents may optionally be further substituted by 1, 2,        or 3 substituents chosen from alkyl, carboxy, carboxyalkyl,        aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted        amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, or        heteroaryl and n is 0, 1 or 2; or    -   2) an alkyl group as defined above that is interrupted by 1-10        atoms (e.g. 1, 2, 3, 4, or 5 atoms) independently chosen from        oxygen, sulfur and NRa—, where Ra is chosen from hydrogen,        alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl,        heteroaryl and heterocyclyl. All substituents may be optionally        further substituted by alkyl, alkoxy, halogen, CF₃, amino,        substituted amino, cyano, or —S(O)_(n)R, in which R is alkyl,        aryl, or heteroaryl and n is 0, 1 or 2; or    -   3) an alkyl group as defined above that has both 1, 2, 3, 4 or 5        substituents as defined above and is also interrupted by 1-10        atoms (e.g. 1, 2, 3, 4, or 5 atoms) as defined above.

The term “lower alkyl” refers to a monoradical branched or unbranchedsaturated hydrocarbon chain having 1, 2, 3, 4, 5, or 6 carbon atoms.This term is exemplified by groups such as methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, t-butyl, n-hexyl, and the like.

The term “substituted lower alkyl” refers to lower alkyl as definedabove having 1 to 5 substituents (typically 1, 2, or 3 substituents), asdefined for substituted alkyl, or a lower alkyl group as defined abovethat is interrupted by 1, 2, 3, 4, or 5 atoms as defined for substitutedalkyl, or a lower alkyl group as defined above that has both 1, 2, 3, 4or 5 substituents as defined above and is also interrupted by 1, 2, 3,4, or 5 atoms as defined above.

The term “alkylene” refers to a diradical of a branched or unbranchedsaturated hydrocarbon chain, typically having from 1 to 20 carbon atoms(e.g. 1-10 carbon atoms, or 1, 2, 3, 4, 5 or 6 carbon atoms). This termis exemplified by groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—), and thelike.

The term “lower alkylene” refers to a diradical of a branched orunbranched saturated hydrocarbon chain, typically having 1, 2, 3, 4, 5,or 6 carbon atoms.

The term “substituted alkylene” refers to:

-   -   (1) an alkylene group as defined above having 1, 2, 3, 4, or 5        substituents (typically 1, 2, or 3 substituents) selected from        the group consisting of alkyl, alkenyl, alkynyl, alkoxy,        cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,        aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,        hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,        heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl,        aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino,        heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino,        alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl,        —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless otherwise        constrained by the definition, all substituents may optionally        be further substituted by 1, 2, or 3 substituents chosen from        alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy,        halogen, CF₃, amino, substituted amino, cyano, and —S(O)_(n)R,        where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2; or    -   (2) an alkylene group as defined above that is interrupted by        1-10 groups (e.g. 1, 2, 3, 4, or 5 groups) independently chosen        from —O—, —S—, sulfonyl, —C(O)—, —C(O)O—, —C(O)N—, and —NRa—,        where Ra is chosen from hydrogen, optionally substituted alkyl,        cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl; or    -   (3) an alkylene group as defined above that has both 1, 2, 3, 4        or 5 substituents as defined above and is also interrupted by        1-10 groups as defined above. Examples of substituted alkylenes        are chloromethylene (—CH(Cl)—), aminoethylene (—CH(NH₂)CH₂—),        methylaminoethylene (—CH(NHMe)CH₂—), 2-carboxypropylene isomers        (—CH₂CH(CO₂H)CH₂—), ethoxyethyl (—CH₂CH₂O—CH₂CH₂—),        ethylmethylaminoethyl (—CH₂CH₂—N(CH₃)—CH₂CH₂—),        1-ethoxy-2-(2-ethoxy-ethoxy)ethane        (—CH₂CH₂O—CH₂CH₂—OCH₂CH₂—OCH₂CH₂—), and the like.

The term “aralkyl” refers to an aryl group covalently linked to analkylene group, where aryl and alkylene are defined herein. “Optionallysubstituted aralkyl” refers to an optionally substituted aryl groupcovalently linked to an optionally substituted alkylene group. Sucharalkyl groups are exemplified by benzyl, phenylethyl,3-(4-methoxyphenyl)propyl, and the like.

The term “alkoxy” refers to the group R—O—, where R is optionallysubstituted alkyl or optionally substituted cycloalkyl, or R is a group—Y—Z, in which Y is optionally substituted alkylene and Z is optionallysubstituted alkenyl, optionally substituted alkynyl; or optionallysubstituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl are as defined herein. Typical alkoxy groups are alkyl-O—and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy,1,2-dimethylbutoxy, and the like.

The term “lower alkoxy” refers to the group R—O— in which R isoptionally substituted lower alkyl as defined above. This term isexemplified by groups such as methoxy, ethoxy, n-propoxy, iso-propoxy,n-butoxy, iso-butoxy, t-butoxy, n-hexyloxy, and the like.

The term “alkylthio” refers to the group R—S—, where R is as defined foralkoxy.

The term “alkenyl” refers to a monoradical of a branched or unbranchedunsaturated hydrocarbon group typically having from 2 to 20 carbon atoms(more typically from 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) andhaving from 1 to 6 carbon-carbon double bonds, e.g. 1, 2, or 3carbon-carbon double bonds. Typical alkenyl groups include ethenyl (orvinyl, i.e. —CH═CH₂), 1-propylene (or allyl, —CH₂CH═CH₂), isopropylene(—C(CH₃)═CH₂), bicyclo[2.2.1]heptene, and the like. In the event thatalkenyl is attached to nitrogen, the double bond cannot be alpha to thenitrogen.

The term “lower alkenyl” refers to alkenyl as defined above having from2 to 6 carbon atoms.

The term “substituted alkenyl” refers to an alkenyl group as definedabove having 1, 2, 3, 4 or 5 substituents (typically 1, 2, or 3substituents), selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “alkynyl” refers to a monoradical of an unsaturatedhydrocarbon, typically having from 2 to 20 carbon atoms (more typicallyfrom 2 to 10 carbon atoms, e.g. 2 to 6 carbon atoms) and having from 1to 6 carbon-carbon triple bonds e.g. 1, 2, or 3 carbon-carbon triplebonds. Typical alkynyl groups include ethynyl (—C≡CH), propargyl (orpropynyl, —C≡CCH3), and the like. In the event that alkynyl is attachedto nitrogen, the triple bond cannot be alpha to the nitrogen.

The term “substituted alkynyl” refers to an alkynyl group as definedabove having 1, 2, 3, 4 or 5 substituents (typically 1, 2, or 3substituents), selected from the group consisting of alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen,hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “aminocarbonyl” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl or where both R groups are joined to form a heterocyclicgroup (e.g., morpholino). Unless otherwise constrained by thedefinition, all substituents may optionally be further substituted by 1,2, or 3 substituents chosen from alkyl, carboxy, carboxyalkyl,aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino, substituted amino,cyano, and —S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0,1 or 2.

The term “ester” or “carboxyester” refers to the group —C(O)OR, where Ris alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl, which may beoptionally further substituted by alkyl, alkoxy, halogen, CF₃, amino,substituted amino, cyano, or —S(O)_(n)Ra, in which Ra is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “acylamino” refers to the group —NRC(O)R where each R isindependently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Allsubstituents may be optionally further substituted by alkyl, alkoxy,halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, in which Ris alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “acyloxy” refers to the groups —OC(O)-alkyl, —OC(O)-cycloalkyl,—OC(O)-aryl, —OC(O)-heteroaryl, and —OC(O)-heterocyclyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “aryl” refers to an aromatic carbocyclic group of 6 to 20carbon atoms having a single ring (e.g., phenyl) or multiple rings(e.g., biphenyl), or multiple condensed (fused) rings (e.g., naphthyl,fluorenyl, and anthryl). Typical aryls include phenyl, fluorenyl,naphthyl, anthryl, and the like.

Unless otherwise constrained by the definition for the aryl substituent,such aryl groups can optionally be substituted with 1, 2, 3, 4 or 5substituents (typically 1, 2, or 3 substituents), selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio,thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1, 2, or 3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2.

The term “aryloxy” refers to the group aryl-O— wherein the aryl group isas defined above, and includes optionally substituted aryl groups asalso defined above. The term “arylthio” refers to the group R—S—, whereR is as defined for aryl.

The term “amino” refers to the group —NH₂.

The term “substituted amino” refers to the group —NRR where each R isindependently selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl provided that both Rgroups are not hydrogen, or a group —Y—Z, in which Y is optionallysubstituted alkylene and Z is alkenyl, cycloalkenyl, or alkynyl. Unlessotherwise constrained by the definition, all substituents may optionallybe further substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “carboxyalkyl” refers to the groups —C(O)O-alkyl,—C(O)O-cycloalkyl, where alkyl and cycloalkyl are as defined herein, andmay be optionally further substituted by alkyl, alkenyl, alkynyl,alkoxy, halogen, CF₃, amino, substituted amino, cyano, or —S(O)_(n)R, inwhich R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.

The term “cycloalkyl” refers to cyclic alkyl groups of from 3 to 20carbon atoms having a single cyclic ring or multiple condensed rings.Such cycloalkyl groups include, by way of example, single ringstructures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, andthe like, or multiple ring structures such as adamantanyl, andbicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an arylgroup, for example indan, and the like.

The term “substituted cycloalkyl” refers to cycloalkyl groups having 1,2, 3, 4 or 5 substituents (typically 1, 2, or 3 substituents), selectedfrom the group consisting of alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino,aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy,keto, thiocarbonyl, carboxy, carboxyalkyl, arylthio, heteroarylthio,heterocyclylthio, thiol, alkylthio, aryl, aryloxy, heteroaryl,aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl,heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl,—SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. The term“substituted cycloalkyl” also includes cycloalkyl groups wherein one ormore of the annular carbon atoms of the cycloalkyl group is a carbonylgroup (i.e. an oxygen atom is oxo to the ring). Unless otherwiseconstrained by the definition, all substituents may optionally befurther substituted by 1, 2, or 3 substituents chosen from alkyl,carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃,amino, substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl,or heteroaryl and n is 0, 1 or 2.

The term “halogen” or “halo” refers to fluoro, bromo, chloro, and iodo.

The term “haloalkyl” refers to alkyl of 1-6 carbon atoms substituted by1, 2, 3, 4, 5, or 6 halo atoms.

The term “acyl” denotes a group —C(O)R, in which R is hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl.

The term “heteroaryl” refers to a group comprising 1 to 15 carbon atomsand 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur withinat least one ring. The term “heteroaryl” is generic to the terms“aromatic heteroaryl” and “partially saturated heteroaryl”. The term“aromatic heteroaryl” refers to a heteroaryl in which at least one ringis aromatic. Examples of aromatic heteroaryls include pyrrole,thiophene, pyridine, quinoline, pteridine. The term “partially saturatedheteroaryl” refers to a heteroaryl having a structure equivalent to anunderlying aromatic heteroaryl which has had one or more double bonds inan aromatic ring of the underlying aromatic heteroaryl saturated.Examples of partially saturated heteroaryls include dihydropyrrole,dihydropyridine, 1,2,3,4-tetrahydronaphthalene.

Unless otherwise constrained by the definition for the heteroarylsubstituent, such heteroaryl groups can be optionally substituted with 1to 5 substituents (typically 1, 2, or 3 substituents) selected from thegroup consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl (an alkyl ester), arylthio, heteroaryl,heteroarylthio, heterocyclylthio, thiol, alkylthio, aryl, aryloxy,aralkyl, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy,heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,—SO-alkyl, —SO-aryl, —SO-heteroaryl, —SO₂-alkyl, SO₂-aryl and—SO₂-heteroaryl. Unless otherwise constrained by the definition, allsubstituents may optionally be further substituted by 1, 2, or 3substituents chosen from alkyl, carboxy, carboxyalkyl, aminocarbonyl,hydroxy, alkoxy, halogen, CF₃, amino, substituted amino, cyano, and—S(O)_(n)R, where R is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl)or multiple condensed rings (e.g., indolizinyl, benzothiazole, orbenzothienyl). Examples of nitrogen heterocyclyls and heteroarylsinclude, but are not limited to, pyrrole, imidazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, and the like as well as N-alkoxy-nitrogencontaining heteroaryl compounds.

The term “heteroaryloxy” refers to the group heteroaryl-O—.

The term “heterocyclyl” refers to a monoradical saturated group having asingle ring or multiple condensed rings, having from 1 to 40 carbonatoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms,selected from nitrogen, sulfur, phosphorus, and/or oxygen within thering.

Unless otherwise constrained by the definition for the heterocyclicsubstituent, such heterocyclic groups can be optionally substituted with1 to 5 substituents (typically 1, 2, or 3 substituents), selected fromthe group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl,carboxy, carboxyalkyl, arylthio, heteroarylthio, heterocyclylthio,thiol, alkylthio, aryl, aryloxy, heteroaryl, aminosulfonyl,aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclooxy,hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-aryl, —SO-heteroaryl,—SO₂-alkyl, SO₂-aryl and —SO₂-heteroaryl. Unless otherwise constrainedby the definition, all substituents may optionally be furthersubstituted by 1, 2, or 3 substituents chosen from alkyl, carboxy,carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF₃, amino,substituted amino, cyano, and —S(O)_(n)R, where R is alkyl, aryl, orheteroaryl and n is 0, 1 or 2. Heterocyclic groups can have a singlering or multiple condensed rings. Preferred heterocyclics includetetrahydrofuranyl, morpholino, piperidinyl, and the like.

The term “thiol” refers to the group —SH.

The term “substituted alkylthio” refers to the group —S-substitutedalkyl.

The term “heteroarylthiol” refers to the group —S-heteroaryl wherein theheteroaryl group is as defined above including optionally substitutedheteroaryl groups as also defined above.

The term “sulfoxide” refers to a group —S(O)R, in which R is alkyl,aryl, or heteroaryl. “Substituted sulfoxide” refers to a group —S(O)R,in which R is substituted alkyl, substituted aryl, or substitutedheteroaryl, as defined herein.

The term “sulfone” refers to a group —S(O)₂R, in which R is alkyl, aryl,or heteroaryl. “Substituted sulfone” refers to a group —S(O)₂R, in whichR is substituted alkyl, substituted aryl, or substituted heteroaryl, asdefined herein.

The term “keto” refers to a group —C(O)—. The term “thiocarbonyl” refersto a group —C(S)—. The term “carboxy” refers to a group —C(O)—OH.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not.

A “substituted” group includes embodiments in which a monoradicalsubstituent is bound to a single atom of the substituted group (e.g.forming a branch), and also includes embodiments in which thesubstituent may be a diradical bridging group bound to two adjacentatoms of the substituted group, thereby forming a fused ring on thesubstituted group.

A compound of a given Formula (e.g. the “compound of Formula (I)”) isintended to encompass the compounds of the invention as disclosed, andthe pharmaceutically acceptable salts, pharmaceutically acceptableesters, hydrates, polymorphs, and prodrugs of such compounds.Additionally, the compounds of the invention may possess one or moreasymmetric centers, and can be produced as a racemic mixture or asindividual enantiomers or diastereoisomers. The number of stereoisomerspresent in any given compound of a given Formula depends upon the numberof asymmetric centers present (there are 2n stereoisomers possible wheren is the number of asymmetric centers). The individual stereoisomers maybe obtained by resolving a racemic or non-racemic mixture of anintermediate at some appropriate stage of the synthesis, or byresolution of the compound by conventional means. The individualstereoisomers (including individual enantiomers and diastereoisomers) aswell as racemic and non-racemic mixtures of stereoisomers areencompassed within the scope of the present invention, all of which areintended to be depicted by the structures of this specification unlessotherwise specifically indicated.

The invention also included compounds of Formula I in which from 1 to nhydrogens attached to a carbon atom is/are replaced by deuterium, inwhich n is the number of hydrogens in the molecule. Such compoundsexhibit increased resistance to metabolism, and are thus useful forincreasing the half life of any compound of Formula I when administeredto a mammal. See, for example, Foster, “Deuterium Isotope Effects inStudies of Drug Metabolism”, Trends Pharmacol. Sci. 5(12):524-527(1984). Such compounds are synthesized by means well known in the art,for example by employing starting materials in which one or morehydrogens have been replaced by deuterium.

“Isomers” are different compounds that have the same molecular formula.

“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. The term “(±)” is used to designate a racemic mixturewhere appropriate.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to the Cahn IngoldPrelog R S system. When the compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown aredesignated (+) or (−) depending on the direction (dextro- orlaevorotary) that they rotate the plane of polarized light at thewavelength of the sodium D line.

The term “therapeutically effective amount” refers to an amount that issufficient to effect treatment, as defined below, when administered to amammal in need of such treatment. The therapeutically effective amountwill vary depending upon the subject and disease condition beingtreated, the weight and age of the subject, the severity of the diseasecondition, the manner of administration and the like, which can readilybe determined by one of ordinary skill in the art.

The term “treatment” or “treating” means any treatment of a disease in amammal, including:

-   -   (i) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   (ii) inhibiting the disease, that is, arresting the development        of clinical symptoms; and/or    -   (iii) relieving the disease, that is, causing the regression of        clinical symptoms.

In many cases, the compounds of this invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.Pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines,di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines,di(substituted alkenyl)amines, tri(substituted alkenyl)amines,cycloalkyl amines, di(cycloalkyl)amines, tri(cycloalkyl)amines,substituted cycloalkyl amines, disubstituted cycloalkyl amine,trisubstituted cycloalkyl amines, cycloalkenyl amines,di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substitutedcycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstitutedcycloalkenyl amines, aryl amines, diaryl amines, triaryl amines,heteroaryl amines, diheteroaryl amines, triheteroaryl amines,heterocyclic amines, diheterocyclic amines, triheterocyclic amines,mixed di- and tri-amines where at least two of the substituents on theamine are different and are selected from the group consisting of alkyl,substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl,heterocyclic, and the like. Also included are amines where the two orthree substituents, together with the amino nitrogen, form aheterocyclic or heteroaryl group.

Specific examples of suitable amines include, by way of example only,isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl)amine,tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, tromethamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine,purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and thelike.

Pharmaceutically acceptable acid addition salts may be prepared frominorganic and organic acids. Salts derived from inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like. Salts derived from organic acids includeacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,malic acid, malonic acid, succinic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid,salicylic acid, and the like.

As used herein, “pharmaceutically acceptable carrier” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

“Coronary diseases” or “cardiovascular diseases” refer to diseases ofthe cardiovasculature arising from any one or more than one of, forexample, heart failure (including congestive heart failure, diastolicheart failure and systolic heart failure), acute heart failure,ischemia, recurrent ischemia, myocardial infarction, arrhythmias, angina(including exercise-induced angina, variant angina, stable angina,unstable angina), acute coronary syndrome, diabetes, and intermittentclaudication.

“Intermittent claudication” means the pain associated with peripheralartery disease. “Peripheral artery disease” or PAD is a type ofocclusive peripheral vascular disease (PVD). PAD affects the arteriesoutside the heart and brain. The most common symptom of PAD is a painfulcramping in the hips, thighs, or calves when walking, climbing stairs,or exercising. The pain is called intermittent claudication. Whenlisting the symptom intermittent claudication, it is intended to includeboth PAD and PVD

Arrhythmia refers to any abnormal heart rate. Bradycardia refers toabnormally slow heart rate whereas tachycardia refers to an abnormallyrapid heart rate. As used herein, the treatment of arrhythmia isintended to include the treatment of supra ventricular tachycardias suchas atrial fibrillation, atrial flutter, AV nodal reentrant tachycardia,atrial tachycardia, and the ventricular tachycardias (VTs), includingidiopathic ventricular tachycardia, ventricular fibrillation,pre-excitation syndrome, and Torsade de Pointes (TdP),

Where a given group (moiety) is described herein as being attached to asecond group and the site of attachment is not explicit, the given groupmay be attached at any available site of the given group to anyavailable site of the second group. For example, a “loweralkyl-substituted phenyl”, where the attachment sites are not explicit,may have any available site of the lower alkyl group attached to anyavailable site of the phenyl group. In this regard, an “available site”is a site of the group at which a hydrogen of the group may be replacedwith a substituent.

Nomenclature

Names of compounds of the present invention are provided using ACD/Namesoftware for naming chemical compounds (Advanced Chemistry Development,Inc., Toronto). Other compounds or radicals may be named with commonnames, or systematic or non-systematic names. The naming and numberingof the compounds of the invention is illustrated with a representativecompound of Formula (I)

which is named{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}aceticacid.

Further Embodiments

In typical embodiments, the compounds provided by the present inventionare effective in the treatment of conditions known to respond toadministration of late sodium channel blockers, including cardiovasculardiseases such as atrial and ventricular arrhythmias, Prinzmetal's(variant) angina, stable angina, unstable angina, ischemia andreperfusion injury in cardiac, kidney, liver and the brain, exerciseinduced angina, congestive heart disease, and myocardial infarction. Insome embodiments, compounds provided by the present invention whichfunction as late sodium channel blockers may be used in the treatment ofdiseases affecting the neuromuscular system resulting in pain, seizures,epilepsy, or paralysis, or in the treatment of diabetes and diseasestates related to diabetes, such as diabetic peripheral neuropathy. Insome embodiments, compounds provided by the present invention whichfunction as late sodium channel blockers may be used in the treatment ofcerebrovascular disorders, such as stroke.

Certain compounds of the invention also possess sufficient activity inmodulating neuronal sodium channels and may have appropriatepharmacokinetic properties such that they may active with regard to thecentral and/or peripheral nervous system. Consequently, some compoundsof the invention may also be of use in the treatment of pain ofneuropathic origin.

In typical embodiments, the present invention is intended to encompassthe compounds disclosed herein, and the pharmaceutically acceptablesalts, pharmaceutically acceptable esters, tautomeric forms, polymorphs,and prodrugs of such compounds. In some embodiments, the presentinvention includes a pharmaceutically acceptable addition salt, apharmaceutically acceptable ester, a hydrate of an addition salt, atautomeric form, a polymorph, an enantiomer, a mixture of enantiomers, astereoisomer or mixture of stereoisomers (pure or as a racemic ornon-racemic mixture) of a compound described herein, e.g. a compound ofFormula (I); such as a compound of Formula (I) named herein.

Combination Therapy

Coronary patients being treated for an acute cardiovascular diseaseevent by administration of late sodium channel blockers often exhibitdiseases or conditions that benefit from treatment with othertherapeutic agents. These diseases or conditions can be of thecardiovascular nature or can be related to pulmonary disorders,metabolic disorders, gastrointestinal disorders and the like.Additionally, some coronary patients being treated for an acutecardiovascular disease event by administration of late sodium channelblockers exhibit conditions that can benefit from treatment withtherapeutic agents that are antibiotics, analgesics, and/orantidepressants and anti-anxiety agents.

Cardiovascular related diseases or conditions that can benefit from acombination treatment of late sodium channel blockers with othertherapeutic agents include, without limitation, angina, including stableangina, unstable angina (UA), exercised-induced angina, variant angina,arrhythmias, intermittent claudication, myocardial infarction includingnon-STE myocardial infarction (NSTEMI), heart failure includingcongestive (or chronic) heart failure, acute heart failure, or recurrentischemia.

Therapeutic agents suitable for treating cardiovascular related diseasesor conditions include anti-anginals, heart failure agents,antithrombotic agents, antiarrhythmic agents, antihypertensive agents,and lipid lowering agents.

The co-administration of late sodium channel blockers with therapeuticagents suitable for treating cardiovascular related conditions allowsenhancement in the standard of care therapy the patient is currentlyreceiving.

Anti-anginals include beta-blockers, calcium channel blockers, andnitrates. Beta blockers reduce the heart's need for oxygen by reducingits workload resulting in a decreased heart rate and less vigorous heartcontraction. Examples of beta-blockers include acebutolol (Sectral),atenolol (Tenormin), betaxolol (Kerlone), bisoprolol/hydrochlorothiazide(Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc),labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL),nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), andtimolol (Blocadren).

Nitrates dilate the arteries and veins thereby increasing coronary bloodflow and decreasing blood pressure. Examples of nitrates includenitroglycerin, nitrate patches, isosorbide dinitrate, andisosorbide-5-mononitrate.

Calcium channel blockers prevent the normal flow of calcium into thecells of the heart and blood vessels causing the blood vessels to relaxthereby increasing the supply of blood and oxygen to the heart. Examplesof calcium channel blockers include amlodipine (Norvasc, Lotrel),bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil),nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine(Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

Agents used to treat heart failure include diuretics, ACE inhibitors,vasodilators, and cardiac glycosides. Diuretics eliminate excess fluidsin the tissues and circulation thereby relieving many of the symptoms ofheart failure. Examples of diuretics include hydrochlorothiazide,metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex),spironolactone (Aldactone), and eplerenone (Inspra).

Angiotensin converting enzyme (ACE) inhibitors reduce the workload onthe heart by expanding the blood vessels and decreasing resistance toblood flow. Examples of ACE inhibitors include benazepril (Lotensin),captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril),lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril(Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril(Mavik).

Vasodilators reduce pressure on the blood vessels by making them relaxand expand. Examples of vasodilators include hydralazine, diazoxide,prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassiumchannel activators, and calcium channel blockers also act asvasodilators.

Cardiac glycosides are compounds that increase the force of the heart'scontractions. These compounds strengthen the pumping capacity of theheart and improve irregular heartbeat activity. Examples of cardiacglycosides include digitalis, digoxin, and digitoxin.

Antithrombotics inhibit the clotting ability of the blood. There arethree main types of antithrombotics—platelet inhibitors, anticoagulants,and thrombolytic agents.

Platelet inhibitors inhibit the clotting activity of platelets, therebyreducing clotting in the arteries. Examples of platelet inhibitorsinclude acetylsalicylic acid (aspirin), ticlopidine, clopidogrel(plavix), dipyridamole, cilostazol, persantine sulfinpyrazone,dipyridamole, indomethacin, and glycoprotein llb/llla inhibitors, suchas abciximab, tirofiban, and eptifibatide (Integrelin). Beta blockersand calcium channel blockers also have a platelet-inhibiting effect.

Anticoagulants prevent blood clots from growing larger and prevent theformation of new clots. Examples of anticoagulants include bivalirudin(Angiomax), warfarin (Coumadin), unfractionated heparin, low molecularweight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytic agents act to break down an existing blood clot. Examplesof thrombolytic agents include streptokinase, urokinase, andtenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic agents are used to treat disorders of the heart rate andrhythm. Examples of antiarrhythmic agents include amiodarone, quinidine,procainamide, lidocaine, and propafenone. Cardiac glycosides and betablockers are also used as antiarrhythmic agents.

Antihypertensive agents are used to treat hypertension, a condition inwhich the blood pressure is consistently higher than normal.Hypertension is associated with many aspects of cardiovascular disease,including congestive heart failure, atherosclerosis, and clot formation.Examples of antihypertensive agents include alpha-1-adrenergicantagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura),prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide),and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, suchas propranolol (Inderal), nadolol (Corgard), timolol (Blocadren),metoprolol (Lopressor), and pindolol (Visken); centralalpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres),clonidine hydrochloride and chlorthalidone (Clorpres, Combipres),guanabenz Acetate (Wytensin), guanfacine hydrochloride (Tenex),methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor),methyldopa and hydrochlorothiazide (Aldoril); combinedalpha/beta-adrenergic antagonists, such as labetalol (Normodyne,Trandate), Carvedilol (Coreg); adrenergic neuron blocking agents, suchas guanethidine (Ismelin), reserpine (Serpasil); central nervoussystem-acting antihypertensives, such as clonidine (Catapres),methyldopa (Aldomet), guanabenz (Wytensin); anti-angiotensin II agents;ACE inhibitors, such as perindopril (Aceon) captopril (Capoten),enalapril (Vasotec), lisinopril (Prinivil, Zestril); angiotensin-IIreceptor antagonists, such as Candesartan (Atacand), Eprosartan(Teveten), Irbesartan (Avapro), Losartan (Cozaar), Telmisartan(Micardis), Valsartan (Diovan); calcium channel blockers, such asverapamil (Calan, Isoptin), diltiazem (Cardizem), nifedipine (Adalat,Procardia); diuretics; direct vasodilators, such as nitroprusside(Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil(Loniten), verapamil; and potassium channel activators, such asaprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

Lipid lowering agents are used to lower the amounts of cholesterol orfatty sugars present in the blood. Examples of lipid lowering agentsinclude bezafibrate (Bezalip), ciprofibrate (Modalim), and statins, suchas atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor,Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin(Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

In this invention, the patient in need of the late sodium channelblocker often suffers from secondary medical conditions such as one ormore of a metabolic disorder, a pulmonary disorder, a peripheralvascular disorder, or a gastrointestinal disorder. Such patients canbenefit from treatment of a combination therapy comprising administeringto the patient the compounds of the invention in combination with atleast one therapeutic agent.

Pulmonary disorder refers to any disease or condition related to thelungs. Examples of pulmonary disorders include, without limitation,asthma, chronic obstructive pulmonary disease (COPD), bronchitis, andemphysema.

Examples of therapeutics agents used to treat pulmonary disordersinclude bronchodilators including beta2 agonists and anticholinergics,corticosteroids, and electrolyte supplements. Specific examples oftherapeutic agents used to treat pulmonary disorders includeepinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil),salmeterol (Serevent, Serevent Diskus), theophylline, ipratropiumbromide (Atrovent), tiotropium (Spiriva), methylprednisolone(Solu-Medrol, Medrol), magnesium, and potassium.

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders includeantihypertensive agents and lipid lowering agents, as described in thesection “Cardiovascular Agent Combination Therapy” above. Additionaltherapeutic agents used to treat metabolic disorders include insulin,sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretinmimetics.

Peripheral vascular disorders are disorders related to the blood vessels(arteries and veins) located outside the heart and brain, including, forexample peripheral arterial disease (PAD), a condition that developswhen the arteries that supply blood to the internal organs, arms, andlegs become completely or partially blocked as a result ofatherosclerosis.

Gastrointestinal disorders refer to diseases and conditions associatedwith the gastrointestinal tract. Examples of gastrointestinal disordersinclude gastroesophageal reflux disease (GERD), inflammatory boweldisease (IBD), gastroenteritis, gastritis and peptic ulcer disease, andpancreatitis.

Examples of therapeutic agents used to treat gastrointestinal disordersinclude proton pump inhibitors, such as pantoprazole (Protonix),lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec),rabeprazole; H2 blockers, such as cimetidine (Tagamet), ranitidine(Zantac), famotidine (Pepcid), nizatidine (Axid); prostaglandins, suchas misoprostoL (Cytotec); sucralfate; and antacids.

Patients presenting with an acute coronary disease event may exhibitconditions that benefit from administration of therapeutic agent oragents that are antibiotics, analgesics, antidepressant and anti-anxietyagents in combination with ranolazine.

Antibiotics are therapeutic agents that kill, or stop the growth of,microorganisms, including both bacteria and fungi. Example of antibioticagents include β-Lactam antibiotics, including penicillins(amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil(Duricef), cephalexin (Keflex), cephradine (Velosef), cefaclor (Ceclor),cefuroxime axtel (Ceftin), cefprozil (Cefzil), loracarbef (Lorabid),cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax),cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenems, andmonobactams; tetracyclines, such as tetracycline; macrolide antibiotics,such as erythromycin; aminoglycosides, such as gentamicin, tobramycin,amikacin; quinolones such as ciprofloxacin; cyclic peptides, such asvancomycin, streptogramins, polymyxins; lincosamides, such asclindamycin; oxazolidinoes, such as linezolid; and sulfa antibiotics,such as sulfisoxazole.

Analgesics are therapeutic agents that are used to relieve pain.Examples of analgesics include opiates and morphinomimetics, such asfentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors.

Antidepressant and anti-anxiety agents include those agents used totreat anxiety disorders, depression, and those used as sedatives andtranquillers. Examples of antidepressant and anti-anxiety agents includebenzodiazepines, such as diazepam, lorazepam, and midazolam;enzodiazepines; barbiturates; glutethimide; chloral hydrate;meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem,Serlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine(Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan); venlafaxine(Effexor XR, Efexor); citalopram (Celexa, Cipramil, Talohexane);paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline(Elavil); and bupropion (Wellbutrin, Zyban).

Pharmaceutical Compositions and Administration

Compounds provided in accordance with the present invention are usuallyadministered in the form of pharmaceutical compositions. This inventiontherefore provides pharmaceutical compositions that contain, as theactive ingredient, one or more of the compounds described, or apharmaceutically acceptable salt or ester thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants. The pharmaceutical compositions may be administered alone orin combination with other therapeutic agents. Such compositions areprepared in a manner well known in the pharmaceutical art (see, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.)

The pharmaceutical compositions may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parenteral, particularly by injection.The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compoundaccording to the present invention in the required amount in theappropriate solvent with various other ingredients as enumerated above,as required, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium andthe required other ingredients from those enumerated above. In the caseof sterile powders for the preparation of sterile injectable solutions,the preferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral administration is another route for administration of compounds inaccordance with the invention. Administration may be via capsule orenteric coated tablets, or the like. In making the pharmaceuticalcompositions that include at least one compound described herein, theactive ingredient is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds are generally administered in a pharmaceutically effectiveamount. Preferably, for oral administration, each dosage unit containsfrom 1 mg to 2 g of a compound described herein, and for parenteraladministration, preferably from 0.1 to 700 mg of a compound a compounddescribed herein. It will be understood, however, that the amount of thecompound actually administered usually will be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, the actualcompound administered and its relative activity, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemasktent, or intermittent positive pressure breathing machine. Solution,suspension, or powder compositions may be administered, preferablyorally or nasally, from devices that deliver the formulation in anappropriate manner.

Synthesis of Compounds of Formula I

The compounds of the invention may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of typical compounds described herein,e.g. compounds having structures described by one or more of Formula(I), may be accomplished as described in the following examples. Ifavailable, reagents may be purchased commercially, e.g. from SigmaAldrich or other chemical suppliers.

General Syntheses:

Typical embodiments of compounds in accordance with the presentinvention may be synthesized using the general reaction schemesdescribed below. It will be apparent given the description herein thatthe general schemes may be altered by substitution of the startingmaterials with other materials having similar structures to result inproducts that are correspondingly different. Descriptions of synthesesfollow to provide numerous examples of how the starting materials mayvary to provide corresponding products. Given a desired product forwhich the substituent groups are defined, the necessary startingmaterials generally may be determined by inspection. Starting materialsare typically obtained from commercial sources or synthesized usingpublished methods. For synthesizing compounds which are embodiments ofthe present invention, inspection of the structure of the compound to besynthesized will provide the identity of each substituent group. Theidentity of the final product will generally render apparent theidentity of the necessary starting materials by a simple process ofinspection, given the examples herein.

Synthetic Reaction Parameters

The terms “solvent,” “inert organic solvent” or “inert solvent” refer toa solvent inert under the conditions of the reaction being described inconjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like). Unless specified to the contrary, thesolvents used in the reactions of the present invention are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

Synthesis of the Compounds of Formula (I)

The compounds of Formula (I) are typically prepared using as a startingmaterial a commercially available starting material such as3,4-dihydroxyquinolin-2(1H)-one substituted at the 6 or 7 position bybromo (compound of formula (1)). As shown in Reaction Schemes I and IIbelow, the compound of formula (1) is then converted to a compound ofFormula (I) in a two step process, attaching the desired R¹ andoptionally substituted phenyl groups R⁴ in any order.

Step 1—Preparation of a Compound of Formula (I) where R¹ is Hydrogen

Attachment of the optionally substituted phenyl group R⁴ is typicallycarried out under conditions known as Suzuki coupling. The bromocompound of formula (1) is reacted with an appropriately substitutedboronic acid derivative, for example with4-trifluoromethoxyphenylboronic acid, in an aqueous solvent mixture, forexample acetonitrile/aqueous sodium carbonate or another suitablesolvent such as N,N-dimethylformamide. The reaction is typicallyconducted in the presence of a metal catalyst attached to an appropriateligand, for example dichlorobis-(triphenylphosphine) palladium(II), at atemperature of about 150° C., under irradiation in a microwave, forabout 10 minutes to about 1 hour. When the reaction is substantiallycomplete, the product of Formula (I) where R¹ is hydrogen is isolated byconventional means, for example by partitioning the crude reactionmixture between ethyl acetate/aqueous sodium hydroxide, separating theorganic layer, removing the solvent under reduced pressure, followed bychromatography of the residue, preferably preparatory TLC.

Step 2—Preparation of a Compound of Formula (I) where R is Other thanHydrogen

Attachment of the R¹ substituent is typically carried out by treatingthe compound of Formula (I) where R¹ is hydrogen with a base such assodium hydride or potassium carbonate in a polar solvent such asN,N-dimethylformamide or tetrahydrofuran. A compound of formula R₄X,where X is halo, preferably chloro or bromo, is added at a temperaturebetween 0° C. and 160° C., preferably at around 25° C., and the mixturemaintained at that temperature for 1 to 40 hours. When the reaction issubstantially complete, the product of Formula (I) where R¹ is otherthan hydrogen is isolated and purified by conventional means, forexample by column chromatography purification or preparative HPLCseparation.

Step 1—Preparation of a Compound of Formula (2)

The compound of formula (1) is converted to a compound of formula (2) asdescribed in Reaction Scheme I, Step 2 above.

Step 2—Preparation of a Compound of Formula (I) where R¹ is Other thanHydrogen

The compound of formula (2) is converted to a compound of Formula (I) asdescribed in Reaction Scheme I, Step 1 above.

Alternative Preparation—Secondary Modification of R¹

It will be appreciated that secondary modification may be made to the R¹moiety after the compound of Formula (I) has been synthesized. This typeof modification generally will involve the use of a protected terminalR¹ amino group. Once the protecting group is removed, the terminal R¹amino group may be modified by reaction with any number of reactantsallowing for the addition of a desired substituent.

In one type of secondary modification, the deprotected compound ofFormula (I) is dissolved in the appropriate non-protic solvent, i.e.,acetonitrile or the like, and then an acidic version of the desiredsubstituents added to the reaction mixture, followed by2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU) and diisopropylethylamine. After briefly heating to approximately50° to 70° C., the reaction mixture is cooled to room temperature andthe precipitated product filtered off and washed with additional solventto provide a compound of Formula (I).

In another example of secondary modification, after the deprotectedcompound of Formula (I) is dissolved in the appropriate non-proticsolvent, for example, acetonitrile, it is placed in a microwave vesselwith methyl formate and heated at 135° C. to 150° C. for 15 to 30minutes. Cooling and filtration provide the desired modified product ofFormula (I)

In still another example of secondary modification, the deprotectedcompound of Formula (I) is dissolved in acetonitrile anddichloromethane. A base such as diisopropylethylamine is then addedalong with [1H]-pyrazole-1-hydroxamidine hydrochloride. The reaction isheated at 30° C. to 50° C. for 15 to 30 minutes. Cooling and filtrationprovides a modified compound of Formula (I).

Alternative Preparation —Synthesis Using Non-Brominated Precursor

The compounds of Formula (I) can also be prepared starting withcommercially available starting materials such as3,4-dihydroxyquinolin-2(1H)one, 3,4-dihydro-1,8-naphthyridin-2(1H)-one,3,4-dihydro-1,7-naphthyridin-2(1H)-one, or3,4-dihydro-1,5-naphthyridin-2(1H)-one. Such compounds are brominatedusing conventional techniques, to provide intermediates of formula I,which are then converted to a compound of Formula (I) s described above.

A typical synthesis using this technique is shown below.

It will be appreciated that bromination may result in the production ofa number of isomeric products any or all of which may be isolated andpurified using conventional techniques.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

EXAMPLE 1

A. Synthesis of a Compound of Formula (I) in which R¹, R², R³, R⁵, andR⁶ are Hydrogen, R⁴ is 6-(3-Fluorophenyl), R⁷ is Hydrogen, and X¹ and X²are both —CH═

To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (1a) (226 mg,1.00 mmol) and 3-fluorophenylboronic acid (210 mg, 1.50 mmol) inN,N-dimethylformamide (10 mL) was added potassium carbonate (415 mg,3.00 mmol) and water (2.0 mL). The reaction mixture was stirred for 5minutes under an atmosphere of dry N₂, and PdCl₂(PPh₃)₂ (35 mg, 0.05mmol) was added. The resulting mixture was heated at 86° C. for 5 hours,cooled, diluted with ethyl acetate (20 mL), filtered through a layer ofcelite which was washed with ethyl acetate (60 mL), the filtratetransferred to a separation funnel, and washed with 2 N potassiumcarbonate (20 mL), followed by 30% ammonium chloride (40 mL), then brine(50 mL). The solvent was removed from the organic layer under reducedpressure, to provide a pale yellow solid. To this crude product wasadded methanol (2 mL), the mixture sonicated, filtered, washed with coldmethanol (3.0 mL), and dried under reduced pressure, to afford6-(3-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one, the compound ofFormula (I) in which R¹ is hydrogen, as a white solid; MS m/z 242.1(M+H), anal HPLC >97% in purity. ¹H NMR (400 MHz; dmso-D6) δ 10.21 (s,1H); 7.58 (d, J=2.1 Hz, 1H); 7.42-7.55 (m, 4H); 7.15 (m, 1H); 6.96 (d,J=8.2 Hz, 1H); 3.42 (t, J=7.6 Hz, 2H); 2.97 (t, J=7.6 Hz, 2H).

B. Synthesis of Additional Compounds of Formula (I) in which R¹ isHydrogen

Similarly, following the procedure of Example 1A, but optionallyreplacing 3-fluorophenyl-boronic acid with other optionally substitutedaryl boronic acids, or optionally replacing the conventional heatingwith microwave heating, the following compounds of Formula (I) in whichR¹ is hydrogen were prepared:

1 6-(3-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one 24-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzamide 36-(4-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one 46-phenyl-3,4-dihydroquinolin-2(1H)-one 54-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile 63-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzamide 76-(2-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one 86-(3-acetylphenyl)-3,4-dihydroquinolin-2(1H)-one 96-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one 106-[4-chloro-3-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)- one 116-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one 122-fluoro-5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile 136-[3-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one 141-(2-hydroxyethyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one 156-(3,4-difluorophenyl)-1-(2-hydroxyethyl)-3,4-dihydroquinolin- 2(1H)-one16 6-(2,4-difluorophenyl)-1-(2-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one 176-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one 186-(4-chlorophenyl)-3,4-dihydroquinolin-2(1H)-one 196-(3-fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one 206-(4-chlorophenyl)-3,4-dihydro-1,8-naphthyridin-2(1H)-one

C. Synthesis of Additional Compounds of Formula (I) in which R isHydrogen

Similarly, following the above procedure, but optionally replacing3-fluorophenyl-boronic acid with other optionally substituted arylboronic acids, or optionally replacing the conventional heating withmicrowave heating, other compounds of Formula (I) in which R¹ ishydrogen are prepared:

D. Synthesis of a Compound of Formula (I) in which R¹ is Methyl, R², R³,R⁵, and R⁶ are Hydrogen, R⁴ is 6-(3-Fluorophenyl), R⁷ is Hydrogen, andX¹ and X² are both —CH═

To a cooled (0° C.) solution of6-(3-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one (48 mg, 0.20 mmol) inanhydrous tetrahydrofuran (2 mL) was added 95% sodium hydride (10 mg,0.40 mmol). The reaction mixture was stirred for 5 minutes, then warmedto 40° C. for 15 minutes under an atmosphere of dry N₂. Iodomethane (142mg, 1.00 mmol) was added, and the resulting mixture was stirred at roomtemperature for 15 hours. Methanol (2 mL) was added, and the mixturestirred for 10 minutes. Solvent was removed from the reaction mixtureunder reduced pressure, ethyl acetate (30 mL) and 30% ammonium chloride(10 mL) were added, the organic phase was washed with water (10 mL), 30%ammonium chloride (15 mL) and brine (15 mL), and the organic layer wasconcentrated under reduced pressure to give6-(3-fluorophenyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one. MS m/z 256.1(M+H), anal HPLC 92% in purity. ¹H NMR (400 MHz; CDCl₃) δ 7.46 (dd,J=8.6 Hz, 2.3 Hz, 1H); 7.30-7.42 (m, 3H); 7.25 (m, 1H); 6.98-7.10 (m,2H); 3.39 (s, 3H); 2.97 (t, J=7.4 Hz, 2H); 2.70 (t, J=7.4 Hz, 2H).

E. Synthesis of Additional Compounds of Formula (I) in which R¹ is Otherthen Hydrogen

Similarly, following the procedure of Example 1D, but optionallyreplacing iodomethane with other optionally substituted alkyl halides,and optionally replacing sodium hydride with other bases such aspotassium carbonate or caesium carbonate, and optionally replacing thereaction condition of room temperature with conventional or microwaveheating, the following compounds of Formula (I) in which R¹ is otherthan hydrogen were prepared:

21 6-(3-fluorophenyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one 22 ethyl[6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate 23ethyl [6-(3,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate24 ethyl{2-oxo-6-[3-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate25 ethyl{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate261-{[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one 276-(2,4-difluorophenyl)-1-(2-methoxyethyl)-3,4-dihydroquinolin-2(1H)-one286-(2,4-difluorophenyl)-1-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-2(1H)-one 29 tert-butyl{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate 30 tert-butyl[6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate 312-{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetamide 321-[2-(morpholin-4-yl)-2-oxoethyl]-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one 33 tert-butyl[6-(4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate 346-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one 351-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl]-6-(4-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one 366-(4-chlorophenyl)-3,4-dihydroquinolin-2(1H)-one 371-(pyridin-3-ylmethyl)-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one 38 6-(4-phenoxyphenyl)-3,4-dihydroquinolin-2(1H)-one 391-[(5-methylisoxazol-3-yl)methyl]-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one 40 tert-butyl[6-(4-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate 413-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile 424,4-dimethyl-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one43 6-[3-(morpholin-4-ylcarbonyl)phenyl]-3,4-dihydroquinolin-2(1H)-one

F. Synthesis of Additional Compounds of Formula (I) in which R¹ is Otherthan Hydrogen

Similarly, following the procedure of Example 1D, but optionallyreplacing iodomethane with other optionally substituted alkyl halides,and optionally replacing sodium hydride with other bases such aspotassium carbonate or caesium carbonate, and optionally replacing thereaction condition of room temperature with conventional or microwaveheating, other compounds of Formula (I) are prepared:

EXAMPLE 2

A. Synthesis of a Compound of Formula (I) in which R¹, R², R³, R⁵, andR⁶ are Hydrogen, R⁴ is 6-(4-Trifluoromethyl)phenyl), R⁷ is Hydrogen, andX¹ and X² are both —CH═

To a solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (2.260 g, 10.00mmol) and 4-(trifluoromethyl)phenyl boronic acid (2.850 g, 15.00 mmol)in N,N-dimethylformamide (50 mL) was added sodium bicarbonate (3.360 g,40.00 mmol) and water (5 mL). The reaction mixture was stirred for 5minutes under an atmosphere of dry N₂, then Pd(PPh₃)₄ (579 mg, 0.50mmol) was added, and the resulting mixture was heated at 70° C. untilthe starting material (6-bromo-3,4-dihydroquinolin-2(1H)-one) was nolonger seen by TLC. The mixture was cooled, diluted with ethyl acetate(50 mL), filtered through a layer of celite, which was washed with 10%N,N-dimethylformamide in ethyl acetate (100 mL), and the filtratetransferred to a separation funnel. The organic phase was washed with 1Nsodium carbonate (100 mL), 30% ammonium chloride (100 mL), and brine(100 mL). Solvent was removed under reduced pressure to provide a yellowsolid. Methanol (5.0 mL) was added, and the mixture sonicated, filtered,washed with methanol (5.0 mL), and dried under reduced pressure toafford 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one(2.184 g, 7.5 mmol, 75%). LCMS mz 292.0 (M+H), anal HPLC ca 94% inpurity, ¹H NMR (400 MHz; CDCl₃) δ 7.98 (s, 1H); 7.66 (m, 4H); 7.40-7.50(m, 2H); 6.86 (d, J=9.0 Hz, 1H); 3.06 (t, J=7.6 Hz, 2H); 2.70 (t, J=7.6Hz, 2H).

B. Synthesis of a Compound of Formula (I) in which R¹ ist-Butoxycarbonylmethyl, R², R³, R⁵, and R⁶ are Hydrogen, R⁴ is6-(4-(Trifluoromethyl)phenyl), R⁷ is Hydrogen, and X¹ and X² are both—CH═

To a solution of6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (291 mg, 1.0mmol) in anhydrous N,N-dimethylformamide (2.5 ml) was added potassiumcarbonate (276 mg, 2.0 mmol), and the mixture stirred at roomtemperature for 5 minutes in a 5 ml Personal Chemistry microwavereaction vial. To the above mixture was added tert-butyl 2-bromoacetate(390 mg, 2.0 mmol), the vial was sealed, and subjected to microwaveirradiation at 120° C. for 5 min, and then at 140° C. for 40 min untilmost of the 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-onewas converted. The reaction mixture was cooled, poured into water (40mL), extracted with ethyl acetate (2×40 mL), the combined organic phasewas washed with water (40 mL), 2N sodium carbonate (10 mL), brine (40mL), dried over sodium sulfate, and the solvent was removed underreduced pressure. The crude product was dissolved in a mixture ofN,N-dimethylformamide-methanol (1 and 2 mL respectively), subjected toreverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) toafford tert-butyl2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate(247 mg, 0.61 mmol, 61%). LCMS mz 350.0 (M-56+H), 428.0 (M+Na), analHPLC >98% in purity, ¹H NMR (400 MHz; CDCl₃) δ 7.67 (m, 4H); 7.40-7.50(m, 2H); 6.86 (d, J=8.6 Hz, 1H); 4.63 (s, 2H); 3.04 (t, J=7.4 Hz, 2H);2.76 (t, J=7.4 Hz, 2H), 1.48 (s, 9H).

C. Synthesis of a Compound of Formula (I) in which R¹ is —CH₇COOH, R²,R³, R⁵, and R⁶ are Hydrogen, R⁴ is 6-(4-(Trifluoromethyl)phenyl), R⁷ isHydrogen, and X¹ and X² are both —CH═

To tert-butyl2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate(202 mg, 0.50 mmol) in a 50 mL round-bottom flask was added 4Nhydrochloric acid in 1,4-dioxane (6.0 mL, 24.0 mmol). The reactionmixture was stirred at room temperature for 4 hours, and the solventremoved under reduced pressure. A second portion of 4N HCl in1,4-dioxane (6.0 mL, 24.0 mmol) was added with stirring for another 13hours, and again the solvent was removed under reduced pressure, toafford2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)aceticacid as a solid (162 mg, 0.46 mmol, 92%). LCMS mz 350.0 (M+H), 372.0(M+Na), anal HPLC >97% in purity, ¹H NMR (400 MHz; CDCl₃) δ 7.67 (m,4H); 7.40-7.50 (m, 2H); 6.92 (d, J=8.6 Hz, 1H); 4.76 (s, 2H); 3.04 (m,2H); 2.79 (m, 2H), 1.48 (s, 9H).

D. Synthesis of a Sodium Salt of Formula (I)

To a solution of2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)aceticacid (34.9 mg, 0.10 mmol) in tetrahydrofuran (1 mL) was added sodiumbicarbonate (8.4 mg, 0.10 mmol) and water (2 mL). The reaction mixturewas stirred at room temperature for 1 hour then freeze dried, to givesodium2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate.

E. Synthesis of Additional Compounds of Formula (I)

Similarly, following the above procedures of Example 2, but optionallyreplacing 4-(trifluoromethyl)phenyl boronic acid with other optionallysubstituted aryl boronic acids, or optionally replacing the conventionalheating with microwave heating, the following compounds of Formula (I)were prepared:

44 {2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid 45 tert-butyl {2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate 46 tert-butyl[6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)- yl]acetate 47tert-butyl [6-(4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate 48[6-(4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid 491-(2-methoxyethyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one 50 tert-butyl{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate 51{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid 52 sodium{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate 53 tert-butyl[6-(3-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)- yl]acetate 54 ethyl{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate 552-[6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)- yl]acetamide56 2-{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetamide 57 2-{6-[4-chloro-3-(trifluoromethyl)phenyl]-2-oxo-3,4-dihydroquinolin-1(2H)-yl}acetamide 58[6-(4-chloro-3-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)- yl]aceticacid 59 [6-(3-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]aceticacid

F. Synthesis of Additional Compounds of Formula (I)

Similarly, following the above procedures of Example 2, but optionallyreplacing 4-(trifluoromethyl)phenyl boronic acid with other optionallysubstituted aryl boronic acids, or optionally replacing the conventionalheating with microwave heating, other compounds of Formula (I) areprepared:

EXAMPLE 3

A. Synthesis of tert-butyl2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate

To a mixture of 95% dry sodium hydride (834 mg, 33.0 mmol) in anhydrousN,N-dimethylformamide (30 mL) at room temperature was added a solutionof 6-bromo-3,4-dihydroquinolin-2(1H)-one (6.780 g, 30.00 mmol) inanhydrous N,N-dimethylformamide (10 mL). The reaction mixture wasstirred for 30 minutes under an atmosphere of dry N₂, followed byaddition of a solution of tert-butyl 2-bromoacetate (7.5 mL, 49.7 mmol)in N,N-dimethylformamide (10 mL). The reaction mixture was stirred atroom temperature until the majority of the starting material wasconverted (confirmed by LCMS). The reaction mixture was quenched withmethanol (40 mL), the mixture concentrated under reduced pressure, thendiluted with ethyl acetate (150 mL). The organic phase was washed withwater (100 mL), 30% ammonium chloride (100 mL) and brine (100 mL),dried, and concentrated under reduced pressure. Ethyl ether (20 mL) wasadded, and the mixture sonicated, filtered, washed with ether (20 mL),and dried to afford tert-butyl2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (7.348 g, 21.6mmol, 72%). LCMS mz 285.9 (M-56+H), 363.9 (M+Na), anal HPLC >97% inpurity. ¹H NMR (400 MHz; CDCl₃) δ 7.30-7.40 (m, 2H); 7.50-6.70 (m, 1H);4.54 (s, 2H); 2.92 (m, 2H); 2.69 (m, 2H), 1.44 (s, 9H).

B. Synthesis of a Compound of Formula (I) in which R¹ ist-Butoxycarbonylmethyl, R², R³, R⁵, and R⁶ are Hydrogen, R⁴ is6-(4-(Trifluoromethyl)phenyl), R⁷ is Hydrogen, and X¹ and X² are both—CH═

To a solution of tert-butyl2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (680 mg, 2.0 mmol)and 4-(trifluoromethyl)phenyl boronic acid (456 mg, 2.4 mmol) inN,N-dimethylformamide (3 mL) in a Biotage microwave vial was addedsodium bicarbonate (605 mg, 7.2 mmol) and water (0.55 mL). The reactionmixture was stirred for 5 minutes under an atmosphere of dry N₂, thenPdCl₂(PPh₃)₂ (59 mg, 0.05 mmol) was added, and the resulting mixture wassealed, subjected to microwave irradiation at 130° C. for 20 minutes.The mixture was then cooled, diluted with ethyl acetate (10 mL),filtered through celite, washed with 10% N,N-dimethylformamide in ethylacetate (80 mL), and transferred to a separation funnel. The organicphase was washed with 1N sodium carbonate (40 mL), 30% ammonium chloride(40 mL) and brine (40 mL), dried and concentrated under reducedpressure. The crude product was purified by preparative HPLC with agradient acetonitrile/water (5-98%) to afford tert-butyl2-(6-bromo-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate (535 mg, 1.32mmol, 66%). LCMS mz 349.9 (M-56+H), 427.9 (M+Na), anal HPLC >97% inpurity, ¹H NMR (400 MHz; CDCl₃) δ 7.67 (m, 4H); 7.40-7.50 (m, 2H); 6.86(d, J=8.6 Hz, 1H); 4.63 (s, 2H); 3.04 (t, J=7.4 Hz, 2H); 2.76 (t, J=7.4Hz, 2H), 1.47 (s, 9H).

C. Synthesis of a Compound of Formula (I) in which R¹ is —CH₂COOH, R²,R³, R⁵, and R⁶ are Hydrogen, R⁴ is 6-(4-(Trifluoromethyl)phenyl), R⁷ isHydrogen, and X¹ and X² are both —CH═

Hydrolysis of the tort butyl protecting group was carried out using themethod described in Example 2C above, to obtain2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)aceticacid.

D. Synthesis of Additional Compounds of Formula (I)

Similarly, following the above procedures of Example 3A and 3B, butoptionally replacing 4-(trifluoromethyl)phenyl boronic acid with otheroptionally substituted aryl boronic acids, or optionally replacing theconventional heating with microwave heating, the following compounds ofFormula (I) were prepared:

602-(2-oxo-6-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)aceticacid 62 tert-butyl{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate 63{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}aceticacid 64 tert-butyl[6-(3-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate 65tert-butyl[6-(4-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate 66tert-butyl[2-oxo-6-(4-phenoxyphenyl)-3,4-dihydroquinolin-1(2H)-yl]acetate 67tert-butyl{6-[4-chloro-3-(trifluoromethyl)phenyl]-2-oxo-3,4-dihydroquinolin-1(2H)-yl}acetate 68[6-(4-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid 69[6-(3,4-dichlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid70 [2-oxo-6-(4-phenoxyphenyl)-3,4-dihydroquinolin-1(2H)-yl]acetic acid712-(6-(4-chloro-3-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)aceticacid 72{4,4-dimethyl-2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid 73[6-(3-chloro-4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]aceticacid 742-(6-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)aceticacid 75 tert-butyl2-(6-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate 76 tert-butyl2-(6-(3,4-dichlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate A2-(2-oxo-6-(4-(trifluoromethoxy)phenyl)-3,4-dihydroquinolin-1(2H)-yl)aceticacid B{7-methoxy-2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid C[6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl]aceticacid

E. Synthesis of Additional Compounds of Formula (I)

Similarly, following the above procedures of Example 3A and 3B, butoptionally replacing 4-(trifluoromethyl)phenyl boronic acid with otheroptionally substituted aryl boronic acids, or optionally replacing theconventional heating with microwave heating, other compounds of Formula(I) are prepared:

EXAMPLE 4

A. Synthesis of a Compound of Formula (4)

To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (3) (16.317 g,100 mmol) in anhydrous isopropanol (200 mL) was added potassiumcarbonate (16.585 g, 120.0 mmol) with stirring under an atmosphere ofdry N₂. The reaction mixture was stirred at room temperature for 30minutes, then iodomethane (10.0 mL, 161.3 mmol) was added slowly. Thereaction was heated to reflux with stirring for 60 hours, cooled, andthe solvent evaporated under reduced pressure. To this residue water(200 mL) was added, and the mixture stirred and sonicated, filtered, andthe pale yellow solid was washed with water (1000 mL), and dried underreduced pressure. To the crude dry solid was added 15% ethyl acetate inn-hexane (150 mL), and the mixture sonicated, filtered, washed withn-hexane (50 mL), and dried under reduced pressure, to afford7-methoxy-3,4-dihydroquinolin-2(1H)-one (15.865 g, 89.5 mmol, 90%), thecompound of formula (4). LCMS mz 178.0 (M+H), 200.0 (M+Na), analHPLC >95% in purity, ¹H NMR (400 MHz; dmso-D6) δ 7.09 (d, J=8.2 Hz, 1H);6.57 (dd, J=8.2 and 2.7 Hz, 1H); 6.48 (d, J=2.7 Hz, 1H); 3.78 (s, 2H);2.90 (t, J=7.0 Hz, 2H); 2.57 (t, J=7.0 Hz, 2H).

B. Synthesis of Compounds of Formulae (5) and (6)

To a suspension of 7-methoxy-3,4-dihydroquinolin-2(1H)-one (3.544 g,20.0 mmol) in hot water (50 mL) was added dropwise a solution of bromine(3.520 g, 22.0 mmol) and potassium bromide (4.8 g, 40.0 mmol) in water(30 mL) under an atmosphere of dry N₂. The reaction mixture was heatedto reflux with stirring for 16 hours, then cooled, sonicated, filtered,the solid washed with water (500 mL), and dried under reduced pressureto afford a white solid (5.036 g, ca 90% yield), which is a mixture of6-bromo-7-methoxy-3,4-dihydroquinolin-2(1H)-one (5) (70% in ¹HNMR) and6,8-dibromo-7-methoxy-3,4-dihydroquinolin-2(1H)-one (6) (30%).

A portion of the mixture thus obtained (3.668 g) was treated with 15%ethyl acetate in n-hexane (20 mL), sonicated, filtered, the solid washedwith n-hexane (20 mL), and dried under reduced pressure, to afford6-bromo-7-methoxy-3,4-dihydroquinolin-2(1H)-one (5) (1.464 g, 5.7 mmol,24%). LCMS mz 255.9 (M−H) and 257.9 (M+H), anal HPLC >94% in purity, ¹HNMR (400 MHz; CDCl₃) δ 7.64 (s, 1H); 7.32 (d, J=0.8 Hz, 1H); 6.29 (s,1H); 3.87 (s, 3H); 2.90 (m, 2H); 2.62 (m, 2H).

C. Synthesis of Compounds of Formulae (7), (8), (9) and (10)

To a solution of the crude mixture of6-bromo-7-methoxy-3,4-dihydroquinolin-2(1H)-one (5) (330 mg, 1.29 mmol)and 6,8-dibromo-7-methoxy-3,4-dihydroquinolin-2(1H)-one (6) (185 mg,0.55 mmol) in N,N-dimethylformamide (2.5 mL) was added4-chlorophenylboronic acid (375 mg, 2.4 mmol), sodium bicarbonate (504mg, 6.0 mmol) and water (0.5 mL) in a Biotage microwave vial. Thereaction mixture was stirred for 5 minutes under an atmosphere of dryN₂, and Pd(PPh₃)₄ (30 mg, 0.025 mmol) was added. The resulting mixturewas sealed, and subjected to microwave irradiation at 130° C. for 30minutes. The product was cooled, diluted with ethyl acetate (10 mL),filtered through celite, washed with 10% N,N-dimethylformamide in ethylacetate (60 mL), and transferred to a separation funnel. The organicphase was washed with 1N sodium carbonate (30 mL), 30% ammonium chloride(30 mL) and brine (30 mL), and dried and concentrated under reducedpressure. The crude product was purified by preparative HPLC with agradient acetonitrile/water (5-98%), and the following four compoundswere separated:

6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (7) (222 mg,0.77 mmol, 60%): LCMS mz 288.0 (M+H), anal HPLC >98% in purity, ¹H NMR(400 MHz; CDCl₃) δ 7.50 (s, 1H); 7.42 (m, 2H); 7.36 (m, 2H); 7.08 (s,1H); 6.34 (s, 1H); 3.78 (s, 3H); 2.95 (t, J=7.2 Hz, 2H); 2.66 (m, 2H).

8-bromo-6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (8)(13 mg, 0.035 mmol): LCMS mz 367.9 (M+H), anal HPLC >96% in purity, ¹HNMR (400 MHz; CDCl₃) δ 7.49 (m, 2H); 7.39 (s, 1H); 7.24 (m, 2H); 7.06(s, 1H); 3.43 (s, 3H); 2.97 (m, 2H); 2.62 (m, 2H).

6-bromo-8-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (9)(9 mg, 0.024 mmol): LCMS mz 367.9 (M+H), anal HPLC >94% in purity, ¹HNMR (400 MHz; CDCl₃) δ7.83 (s, 1H); 7.50 (m, 2H); 7.40 (m, 2H); 7.04 (s,1H); 3.44 (s, 3H); 3.01 (m, 2H); 2.64 (m, 2H).

6,8-bis(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (10) (80mg, 0.20 mmol): LCMS mz 399.9 (M+H), anal HPLC >98% in purity, ¹H NMR(400 MHz; CDCl₃) δ7.46-7.52 (m, 4H); 7.36-7.42 (m, 2H); 7.26-7.32 (m,2H); 7.16 (s, 1H); 7.12 (s, 1H); 3.08 (s, 3H); 3.02 (m, 2H); 2.66 (m,2H).

D. Synthesis of a Compound of Formula (I) in which R¹ ist-Butoxycarboxymethyl, R², R³, R⁵, and R⁶ are Hydrogen, R⁴ is6-(4-chloromethyl)phenyl), R⁷ is Methoxy, and X¹ and X² are both —CH═

To a mixture of 95% dry sodium hydride (24 mg, 1.00 mmol) in anhydrousN,N-dimethylformamide (8 mL) at room temperature was added a solution of6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (7) (110 mg,0.38 mmol) in N,N-dimethylformamide. The reaction mixture was stirredfor 30 minutes under an atmosphere of dry N₂, followed by addition of asolution of tert-butyl bromoacetate (390 mg, 2.00 mmol) inN,N-dimethylformamide (2 mL). The reaction mixture was stirred at roomtemperature until majority of the starting material was converted (asshown by LCMS), then it was quenched by addition of methanol (10 mL).The mixture was concentrated under reduced pressure, anhydrous toluene(10 mL) was added to the residue, and the solvent removed under reducedpressure, to afford crude (tert-butyl2-(6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate).

Synthesis of a Compound of Formula (I) in which R¹ is —CH₂COOH

To the crude (tert-butyl2-(6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate)form Example 4D was added 4N hydrochloric acid in 1,4-dioxane (10 mL, 40mmol). The reaction mixture was stirred at room temperature for 4 hours,and concentrated under reduced pressure. A second portion of 4Nhydrochloric acid in 1,4-dioxane (10 mL, 40 mmol) and anhydrousN,N-dimethylformamide (2 mL) were added, and the mixture stirred foranother 13 hours. The solvent was removed under reduced pressure, andthe crude reaction product subjected to reverse phase HPLC with agradient of acetonitrile/water (2% to 98%) to afford2-(6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)aceticacid (95 mg, 0.27 mmol, 72%). LCMS mz 346.0 (M+H), 368.0 (M+Na), analHPLC >98% in purity. ¹H NMR (400 MHz; CDCl₃) δ 7.42 (d, J=8.6 Hz, 2H);7.36 (d, J=8.6 Hz, 2H); 7.11 (s, 1H); 6.48 (s, 1H); 4.75 (s, 2H); 3.79(s, 3H); 2.93 (m, 2H); 2.75 (m, 2H).

F. Synthesis of Additional Compounds of Formula (I)

Similarly, following the above procedure from Example 4A, 4B, 4C, 4D and4E but optionally replacing 4-chlorophenyl boronic acid with otheroptionally substituted aryl boronic acids, the following compounds ofFormula (I) were prepared:

77 6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one 788-bromo-6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one 792-(7-methoxy-2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetic acid 802-(6-(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)aceticacid 812-(6,8-bis(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)aceticacid 826-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one83 7-methoxy-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one84 6,8-bis(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one 85tert-butyl-2-(7-methoxy-2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate

G. Synthesis of Additional Compounds of Formula (I)

Similarly, following the above procedure from Example 4A, 4B, 4C, 4D and4E, but optionally replacing 4-chlorophenylboronic acid with otheroptionally substituted aryl boronic acids, other compounds of Formula(I) are prepared:

EXAMPLE 5

A. Preparation of a Compound of Formula (4)

To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (2.015 g, 12.35mmol) in anhydrous N,N-dimethylformamide (25 mL) was added potassiumcarbonate (1.880 g, 13.60 mmol) with stirring, and tert-butyl4-(bromomethyl)benzoate (2.960 g, 10.83 mmol) in N,N-dimethylformamide(10 mL) was added. The reaction mixture was stirred at room temperaturefor 30 minutes, then heated to 60° C. for 72 hours. The mixture wascooled, the solvent volume reduced to half under reduced pressure, andthe residue poured slowly into water (100 mL) with stirring. Diethylether (5 mL) was added, the mixture sonicated, filtered, and the whitesolid thus obtained was washed with saturated sodium carbonate (60 mL),water (200 mL), diethyl ether (15 mL), and dried to afford tert-butyl4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoate (2.122 g,6.00 mmol, 55%). LCMS mz 376.0 (M+Na), anal HPLC >92% in purity, ¹H NMR(400 MHz; CDCl₃) 8.00 (d, J=8.6 Hz, 1H); 7.55 (s, 2H); 7.45 (d, J=8.6Hz, 2H); 7.05 (d, J=8.2 Hz, 1H); 6.57 (dd, J=8.4 and 2.5 Hz, 1H); 6.35(d, J=2.3 Hz, 1H); 2.90 (m, 2H); 2.61 (m, 2H); 1.60 (s, 9H).

B. Preparation of a Compound of Formula (5)

To a suspension of tert-butyl4-((2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoate (550 mg,1.56 mmol) in glacial acetic acid (5 mL) was added dropwise a solutionof bromine (800 mg, 5.00 mmol) and potassium bromide (595 mg, 5.0 mmol)in acetic acid (10 mL) under an atmosphere of dry N₂, and the mixturestirred at room temperature for 1 hour. The reaction mixture was warmedto 60° C. for 18 hours, then cooled, and the solvent evaporated underreduced pressure. The residue was poured slowly into water (40 mL) withstirring, diethyl ether (3 mL) was added, and the mixture sonicated,filtered, the solid thus obtained was washed with saturated sodiumcarbonate (30 mL), water (50 mL), diethyl ether (10 mL), and dried underreduced pressure to afford4-((6-bromo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoic acid(334 mg, 0.89 mmol, 57%). LCMS mz 375.9 (M−H) and 377.9 (M+H), analHPLC >91% in purity, ¹H NMR (400 MHz; CD₃CN) δ8.25 (bs, 1H); 8.09 (d,J=8.6 Hz, 2H); 7.65 (d, J=8.6 Hz, 2H); 7.42 (s, 1H); 6.62 (s, 1H); 5.26(s, 2H); 2.91 (m, 2H); 2.53 (m, 2H).

C. Preparation of a Compound of Formula (I)

To a solution of4-((6-bromo-2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoic acid(100 mg, 0.27 mmol) and 4-chlorophenyl boronic acid (62 mg, 0.40 mmol)in N,N-dimethylformamide (2.0 mL) in a Biotage microwave vial was addedsodium bicarbonate (200 mg, 2.38 mmol) and water (0.50 mL). The reactionmixture was stirred for 5 minutes under an atmosphere of dry N₂.Pd(PPh₃)₄ (10 mg, 0.009 mmol) was added, and the resulting mixture wassealed and subjected to microwave irradiation at 130° C. for 8 minutes.The mixture was cooled, diluted with ethyl acetate (5 mL), filteredthrough celite, washed with 10% N,N-dimethylformamide in ethyl acetate(40 mL), transferred to a separation funnel, and the organic phase waswashed with 1N sodium carbonate (20 mL), 30% ammonium chloride (20 mL)and brine (30 mL), dried and the solvent removed under reduced pressure.The crude product was purified by preparative HPLC with a gradientacetonitrile/water (5-98%) to afford4-((6-(4-chlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoicacid (72 mg, 0.18 mmol, 66%). LCMS mz 408.0 (M+H), 430.0 (M+Na), analHPLC >96% in purity, ¹H NMR (400 MHz; dmso-D6) δ10.1 (σ, 1H), 7.95 (d,J=8.2 Hz, 2H); 7.55 (d, J=9.0 Hz, 2H); 7.48 (m, 4H); 7.18 (s, 1H); 6.69(s, 1H); 5.15 (s, 2H); 2.87 (m, 2H); 2.47 (m, 2H).

D. Preparation of other Compounds of Formula (I)

Similarly, following the procedures of Example 5A, 5B, and 5C, butoptionally replacing tert-butyl 4-(bromomethyl)benzoate with tert-butylbromoacetate, or replacing 4-chlorophenyl boronic acid with otheroptionally substituted aryl boronic acids, the following compounds ofFormula I were prepared:

-   4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-7-yloxy)methyl)benzoic    acid;-   2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinolin-7-yloxy)acetic    acid;-   2-(2-oxo-6-(4-phenoxyphenyl)-1,2,3,4-tetrahydroquinolin-7-yloxy)acetic    acid; and-   2-(6-(4-chlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)acetic    acid.

EXAMPLE 6

A. Synthesis of a Compound of Formula (I) in which R¹ is Cyanomethyl

To a mixture of 95% dry sodium hydride (48 mg, 2.00 mmol) in anhydrousN,N-dimethylformamide (10 mL) at room temperature was added a solutionof 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (291 mg,1.00 mmol). The reaction mixture was stirred for 30 minutes under anatmosphere of dry N₂, followed by addition of a solution of2-bromoacetonitrile (480 mg, 4.00 mmol) in N,N-dimethylformamide (2 mL).The reaction mixture was stirred at room temperature until the majorityof the starting material was converted (as checked by LCMS), thenquenched by addition of methanol (10 mL). The mixture was concentratedunder reduced pressure, and the residue was subjected to reverse phaseHPLC with a gradient of acetonitrile/water (2% to 98%) to afford2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetonitrile(compound No. 90) (307 mg, 0.93 mmol, 93%). LCMS mz 331.0 (M+H), 353.0(M+Na), anal HPLC >98% in purity. ¹H NMR (400 MHz; CDCl₃) δ 7.69 (m,4H); 7.57 (dd, J=8.4 and 2.1 Hz, 1H); 7.47 (d, J=3.0 Hz, 1H); 7.16 (d,J=8.2 Hz, 1H); 6.90 (s, 2H); 3.05 (m, 2H); 2.79 (m, 2H).

B. Synthesis of Compounds of Formula (I) in which R¹ is Tetrazolylmethyl

A Biotage microwave vial was charged with2-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetonitrile(66 mg, 0.20 mmol), azidotrimethylsilane (46 mg, 0.40 mmol), dibutyltinoxide (8 mg, 0.03 mmol), and anhydrous N,N-dimethylformamide (2.5 mL),and the vial capped. The reaction mixture was heated to 160° C. andirradiated for 25 minutes. LCMS showed only ca 63% conversion.Additional azidotrimethylsilane (46 mg, 0.40 mmol) was added, and heatedagain at 160° C. for an additional 30 minutes. LCMS showed thedisappearance of starting material. The reaction mixture was dilutedwith ethyl acetate (30 mL), washed with 30% aqeuous ammonium chloride(2×10 mL), brine (20 mL), and dried over sodium sulfate. The solvent wasremoved from the solution under reduced pressure to give a pale yellowsolid. Ethyl ether (3 mL) was added, sonicated, filtered, washed withethyl ether (10 mL), dried to afford1-((2H-tetrazol-5-yl)methyl)-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-oneas a white solid (59 mg, 0.16 mmol, 80%). LCMS mz 374.0 (M+H), analHPLC >97% purity, ¹HNMR (400 MHz, CD₃CN) δ 7.83 (m, 4H); 7.65 (d, J=2.0Hz, 1H); 7.62 (dd, J=8.4 and 2.1 Hz, 1H); 7.30 (d, J=8.6 Hz, 1H); 5.46(s, 2H); 3.11 (m, 2H); 2.77 (m, 2H).

C. Synthesis of Additional Compounds of Formula (I)

Similarly, following the above procedures of Example 6A and 6B, butoptionally replacing6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one with otheroptionally substituted aryl-3,4-dihydroquinolin-2(1H)-one, othercompounds of Formula (I) are prepared:

EXAMPLE 7

A. Synthesis of a Compound of Formula (I) in which R¹ is4-(t-Butoxycarbonyl)-phenylmethyl

To a mixture of 95% dry sodium hydride (12 mg, 0.50 mmol) in anhydrousN,N-dimethylformamide (4 mL) at room temperature was added a solution of6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (78 mg, 0.30mmol) (PT-010 made as in Example 1B, above) in anhydrousN,N-dimethylformamide (1 mL). The reaction mixture was stirred for 30minutes under an atmosphere of dry N₂, followed by addition of asolution of tert-butyl 4-(bromomethyl)benzoate (271 mg, 1.00 mmol) inN,N-dimethylformamide (1.0 mL). The reaction mixture was stirred at roomtemperature until the majority of the starting material was converted(checked by LCMS), then it was quenched by addition of methanol (5 mL).The reaction mixture was concentrated under reduced pressure, anhydroustoluene (10 mL) was added, and the solvent removed under reducedpressure. To this crude product (tert-butyl4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate)was added 4N hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol). Thereaction mixture was stirred at room temperature for 4 hours, and thesolvent removed under reduced pressure. A second portion of 4Nhydrochloric acid in 1,4-dioxane (10 mL, 40 mmol) was added withstirring at room temperature for another 13 hours, the solvent removedunder reduced pressure. The crude reaction product was subjected toreverse phase HPLC with a gradient of MeCN/H₂O (2% to 98%) to afford4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoicacid (70 mg, 0.16 mmol, 53%) (PT-088). LCMS mz 488.0 (M+H), 510.0(M+Na), anal HPLC >98% in purity. ¹H NMR (400 MHz; DMSO-d6) δ 7.90 (d,J=8.2 Hz, 2H); 7.86 (d, J=8.2 Hz, 2H); 7.78 (d, J=8.2 Hz, 2H); 7.68 (d,J=2.1 Hz, 1H); 7.53 (dd, J=8.3 and 2.1 Hz, 1H); 7.38 (d, J=8.2 Hz, 2H);7.00 (d, J=8.6 Hz, 1H); 5.27 (s, 2H); 3.08 (m, 2H), 2.79 (m, 2H).

B. Synthesis of Additional Compounds of Formula (I)

Similarly, following the above procedure of Example 7A, but optionallyreplacing 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-onewith another optionally substituted6-phenyl-3,4-dihydroquinolin-2(1H)-one derivative, or optionallyreplacing the tert-butyl 4-(bromomethyl)benzoate with other optionallysubstituted bromomethylbenzene compounds, the following compounds ofFormula (I) were prepared.

86 4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoic acid 87 methyl4-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate

C. Synthesis of Additional Compounds of Formula (I)

Similarly, following the above procedure of Example 7A, but optionallyreplacing 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-onewith another optionally substituted6-phenyl-3,4-dihydroquinolin-2(1H)-one derivatives, or optionallyreplacing the tert-butyl 4-(bromomethyl)benzoate with other optionallysubstituted bromomethylbenzene compounds, other compounds of Formula (I)are prepared.

EXAMPLE 8

A. Synthesis of a Compound of Formula (I) in which R¹ is3-Ethoxycarbonyl)-phenylmethyl

To a mixture of 95% dry sodium hydride (18 mg, 0.75 mmol) in anhydrousN,N-dimethylformamide (4 mL) at room temperature was added a solution of6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (90 mg, 0.31mmol) (PT-010 made as in Example 1B, above) in anhydrousN,N-dimethylformamide (1 mL). The reaction mixture was stirred for 30minutes under an atmosphere of dry N₂, followed by addition of asolution of ethyl 3-(chloromethyl)benzoate (100 mg, 1.00 mmol) inN,N-dimethylformamide (1.0 mL). The reaction mixture was stirred at roomtemperature until most of the starting material was converted (checkedby LCMS), then it was quenched by addition of methanol (5 mL). Thereaction mixture was concentrated under a reduced pressure, diluted withethyl acetate (50 mL), and the organic phase washed with 2N sodiumcarbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL), driedover magnesium sulfate, and the solvent removed under reduced pressure.The residue was dissolved in N,N-dimethylformamide (3 mL) and subjectedto reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%)to afford ethyl3-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate(compound no. 91) (108 mg, 0.24 mmol, 77%) (PT-094). LCMS mz 455.0(M+H), 476.0 (M+Na), anal HPLC >95% in purity. ¹H NMR (400 MHz; CDCl₃) δ7.94 (m, 2H); 7.64 (m, 4H); 7.41 (m, 3H); 7.30-7.37 (m, 1H); 6.92 (d,J=8.6 Hz, 1H); 5.27 (s, 2H); 4.37 (q, J=7.0 Hz, 2H); 3.08 (m, 2H), 2.86(m, 2H); 1.39 (t, J=7.0 Hz, 3H).

B. Synthesis of a Compound of Formula (I)—Hydrolysis of Ester

To a solution of ethyl3-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoate(45 mg, 0.10 mmol) (PT-094) in N,N-dimethylformamide (2.0 mL) was added1N potassium hydroxide in methanol (10 mL, 10 mmol). The reactionmixture was stirred at room temperature for 17 hours, and then thesolvent was removed under reduced pressure. Water (5.0 mL) was added,and the pH was adjusted to 4-5. The mixture was extracted with ethylacetate (3×20 mL), and the combined organic phase was washed with 30%ammonium chloride (20 mL), brine (20 mL), dried over magnesium sulfate,and the solvent removed under reduced pressure. The residue wassubjected to reverse phase HPLC with a gradient of acetonitrile/water(2% to 98%) to afford3-((2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)methyl)benzoicacid (26 mg, 0.06 mmol, 60%) (PT-095). LCMS mz 426.0 M+H), 448.0 (M+Na).¹H NMR (400 MHz; CDCl₃) δ 8.06 (bs, 2H); 7.65 (m, 4H); 7.47 (m, 3H);7.36 (m, 1H); 6.92 (d, J=8.6 Hz, 1H); 5.28 (s, 2H); 3.08 (m, 2H), 2.86(m, 2H).

C. Synthesis of Additional Compounds of Formula (I)

Similarly, following the procedures of Example 8A and 8B, but optionallyreplacing 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-onewith other optionally substituted 6-phenyl-3,4-dihydroquinolin-2(1H)-onederivatives, or optionally replacing the ethyl 3-(chloromethyl)benzoatewith other optionally substituted chloromethylbenzene compounds, othercompounds of Formula (I) are prepared.

EXAMPLE 9

A. Synthesis of a Compound of Formula (I) in which R¹ is2-hydroxy-3-2-methoxyphenoxy)propyl)

To a solution of 6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one(180 mg, 0.69 mmol) (PT-012, made as in Example 1B, above) and2-((2-methoxyphenoxy)methyl)oxirane (162 mg, 0.90 mmol) in anhydrousN,N-dimethylformamide (2 ml) was added caesium carbonate (326 mg, 1.00mmol) in a 5 ml Personal Chemistry microwave reaction vial. The reactionvial was sealed, and subjected to microwave irradiation at 180° C. for40 minutes. The reaction was cooled, poured into water (10 mL),extracted with ethyl acetate (2×30 mL), and the combined organic phaseswashed with water (30 mL), 2N sodium carbonate (30 mL), brine (40 mL),dried over sodium sulfate, and the solvent removed under reducedpressure. The residue was subjected to reverse phase HPLC with agradient of acetonitrile/water (2% to 98%) to afford6-(2,4-difluorophenyl)-1-(2-hydroxy-3-(2-methoxyphenoxy)propyl)-3,4-dihydroquinolin-2(1H)-one(148 mg, 0.34 mmol, 49%) (compound No. 88)). LCMS mz 440.0 (M+H), 462.0(M+Na), anal HPLC >95% in purity. ¹H NMR (400 MHz; CDCl₃) δ 7.46 (d,J=8.6 Hz, 1H); 7.36 (m, 2H); 7.31 (bs, 1H); 6.88-7.03 (m, 6H); 4.36 (m,H); 4.27 (s, 1H), 4.26 (d, J=2.3 Hz, 1H); 4.15 (dd, J=9.8 and 5.5 Hz,1H); 4.00-4.10 (m, 2H); 3.88 (s, 3H), 2.99 (m, 2H); 2.76 (m, 2H).

B. Synthesis of Further Compounds of Formula (I)

Similarly, following the procedure of Example 9A, the following compoundof Formula (I) was prepared:

1-(2-hydroxypropyl)-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one(compound no. 89)

C. Synthesis of Additional Compounds of Formula (I)

Similarly, following the procedure of Example 9A, but optionallyreplacing 6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one withanother optionally substituted 6-phenyl-3,4-dihydroquinolin-2(1H)-onederivative, or optionally replacing the24(2-methoxyphenoxy)methyl)oxirane with other optionally substitutedoxirane compounds, other compounds of Formula (I) are prepared.

EXAMPLE 10

Preparation of a Compound of Formula (I) in which R¹ is Ethyl PropionateA. Preparation of ethyl3-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)propanoate

To a solution of6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one, prepared asdescribed above (90 mg, 0.31 mmol) in anhydrous tetrahydrofuran (3 mL)was added at room temperature 20-40 mesh beads of sodium hydroxide (48mg, 1.20 mmol) and ethyl acrylate (1.200 g, 1.20 mmol) in anhydrousN,N-dimethylformamide (1 mL). The reaction mixture was stirred for 4hours under an atmosphere of dry N₂, followed by addition of a secondportion of sodium hydroxide (96 mg, 2.40 mmol). The reaction wasfollowed by LCMS and stirring was continued until all of the startingmaterial had disappeared. Solvent was removed from the reaction mixtureunder reduced pressure, diluted with ethyl acetate (20 mL), and aqueousNa₂SO₃ (10 mL) added. The aqueous phase was extracted with ethyl acetate(3×20 mL), and the combined organic phase successively washed with 2Nsodium carbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL),and dried over magnesium sulfate. Evaporation of the solvent gave acrude mixture that was purified by reverse phase HPLC with a gradient ofacetonitrile/water (2% to 98%) to afford ethyl3-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)propanoate(65 mg, 0.18 mmol, 58%). LCMS mz 364.0 (M+H), 386.0 (M+Na), analHPLC >99% in purity. ¹H NMR (400 MHz; CD₃CN) δ7.87 (d, J=8.2 Hz, 2H);7.81 (d, J=8.6 Hz, 2H); 7.66 (d, J=2.3 Hz, 1H); 7.63 (m, 1H); 7.26 (d,J=8.6 Hz, 1H); 4.25 (m, 2H); 3.02 (m, 2H); 2.67 (m, 4H).

HPLC also afforded a minor amount of3-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)propanoicacid (23 mg, 0.06 mmol, 19%). %). LCMS mz 392.0 (M+H), 414.0 (M+Na),anal HPLC >98% in purity. ¹H NMR (400 MHz; CD₃CN) δ7.83 (m, 4H); 7.63(m, 2H); 7.26 (d, J=8.6 Hz, 1H); 4.26 (t, J=7.2 Hz, 2H); 4.13 (m, 2H);3.00 (m, 2H); 2.66 (m, 4H); 1.25 (t, J=7.0 Hz, 3H).

B. Preparation of other Compounds of Formula (I) in which R¹ is an Ester

Similarly, following the above procedure of Example 10A, but optionallyreplacing 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one(202) with other 3,4-dihydroquinolin-2(1H)-one, or replacing ethylacrylate with other tert-butyl acrylate, or performing a NaOH catalyzedester hydrolysis of the intermediate3-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)propanoate, the followingcompounds of Formula I were prepared:

3-(7-methoxy-2-oxo-6-(4-phenoxyphenyl)-3,4-dihydroquinolin-1(2H)-yl)propanoicacid;

3-(7-methoxy-2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)propanoic acid; and

3-(2-oxo-7-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)propanoic acid.

EXAMPLE 11

Preparation of a Compound of Formula (I) in which R¹ is Benzyl A.Preparation of1-benzyl-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one

To a solution of 6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one(130 mg, 0.50 mmol) in anhydrous tetrahydrofuran (5 mL) at 0° C. in adry flask equipped with an inlet of dry nitrogen was added fresh 1.6 Mn-butyl lithium in n-hexane (0.6 mL, 0.96 mmol) with stirring. Thereaction mixture was stirred at 0° C. for 2 hours, followed by additionof a second portion of 1.6 M n-butyl lithium in n-hexane (0.6 mL, 0.96mmol), and the mixture stirred for another 2 hours. To this mixture wasadded slowly a solution of benzyl bromide (855 mg, 5.00 mmol) inanhydrous tetrahydrofuran (3 mL) at 0° C., stirred overnight, andallowed to warm to room temperature. The reaction was followed by LCMSand stirring was continued until all of the starting material wasconsumed. The reaction mixture was quenched by slow addition ofsaturated aqueous ammonium chloride (10 mL) with stirring, concentratedunder reduced pressure, diluted with ethyl acetate (20 mL) and diluteaqueous ammonium chloride (10 mL). The aqueous phase was extracted withethyl acetate (3×20 mL), and the combined organic phase successivelywashed with 2N sodium carbonate (20 mL), 30% ammonium chloride (20 mL),brine (20 mL), and dried over magnesium sulfate. Evaporation of thesolvent under reduced pressure gave a crude mixture, which was purifiedby reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%)to afford 1-benzyl-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one(62 mg, 0.18 mmol, 35%). LCMS mz 350.0 (M+H), 372.0 (M+Na), analHPLC >98% in purity. ¹H NMR (400 MHz; CDCl₃) δ7.10-7.40 (m, 8H);6.80-7.00 (m, 3H); 5.22 (s, 2H); 3.05 (m, 2H); 2.85 (m, 2H).

HPLC also gave1,3-dibenzyl-6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one (22mg, 0.05 mmol, 10%). LCMS mz 440.0 (M+H), 462.0 (M+Na), anal HPLC >99%in purity. ¹H NMR (400 MHz; CDCl₃) δ7.10-7.40 (m, 13H); 6.90-7.00 (m,3H); 5.24 (m, 2H); 3.42 (dd, J=13.5 and 4.1 Hz, 1H); 2.80-3.10 (m, 2H);2.60-2.75 (m, 2H).

EXAMPLE 12

Preparation of a Compound of Formula (I) in which R¹ is2,4-Difluorobenzyl, R⁵ is —CH₂CO₂H, R⁴ is 3-Fluoro-4-trifluoromethyl,and R⁷ is Methoxy A. Preparation of1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one

To a suspension of 95% sodium hydride in anhydrous N,N-dimethylformamide(2 mL) at room temperature in a dry flask equipped with an inlet of drynitrogen was added a solution of6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one,prepared a shown above (53 mg, 0.10 mmol) in N,N-dimethylformamide (1mL) with stirring. The reaction mixture was stirred for 30 minutes,followed by addition of 1-(bromomethyl)-2,4-difluorobenzene (207 mg, 1.0mmol), and the reaction mixture stirred overnight. The reaction wasfollowed by LCMS and stirring was continued as needed until the startingmaterial was consumed. The reaction mixture was quenched by addition ofsaturated aqueous ammonium chloride (5 mL) with stirring, concentratedunder reduced pressure, diluted with ethyl acetate (20 mL) and diluteaqueous ammonium chloride (10 mL). The aqueous phase was extracted withethyl acetate (3×20 mL), and the combined organic phase was successivelywashed with 2N sodium carbonate (20 mL), 30% aqueous ammonium chloride(20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation ofthe solvent under reduced pressure gave a crude mixture that waspurified by reverse phase HPLC with a gradient of acetonitrile/water (2%to 98%) to afford1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one(25 mg, 0.05 mmol, 52%). LCMS mz 466.0 (M+H), 487.9 (M+Na), analHPLC >98% in purity. ¹H NMR (400 MHz; CDCl₃) δ7.58 (t, J=7.8 Hz, 1H);7.34 (m, 2H); 7.21 (m, 1H); 7.10 (s, 1H); 6.80-6.89 (m, 2H); 6.57 (s,1H); 5.24 (s, 2H); 3.70 (s, 3H); 2.94 (m, 2H); 2.81 (m, 2H).

B. Preparation of tert-butyl2-(1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate

To a solution of1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one(14 mg, 0.03 mmol) in anhydrous tetrahydrofuran (1 mL) at −78° C. in adry flask equipped with an inlet of dry nitrogen was added fresh 1.6 Mn-butyl lithium in n-hexane (40 μL, 0.06 mmol) with stirring. Thereaction mixture was stirred at −78° C. for 30 minutes, then at 0° C.for 1 hour. The reaction mixture was re-cooled to −78° C., a solution oftert-butyl bromoacetate (98 mg, 0.50 mmol) in anhydrous tetrahydrofuranadded (0.5 mL), and the reaction mixture stirred overnight, allowing itto warm up to room temperature. The reaction was followed by LCMS, andstirring was continued as needed until the starting material wasconsumed. The reaction mixture was quenched by addition of saturatedaqueous ammonium chloride (5 mL) with stirring, concentrated underreduced pressure, diluted with ethyl acetate (10 mL) and diluted withaqueous ammonium chloride (5 mL). The aqueous phase was extracted withethyl acetate (3×10 mL), and the combined organic phase was successivelywashed with 2N spdium carbonate (10 mL), 30% ammonium chloride (10 mL),brine (20 mL), and dried over magnesium sulfate. Evaporation of thesolvent under reduced pressure gave a crude mixture which was purifiedby reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%)to afford tert-butyl2-(1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate(12 mg, 0.02 mmol, 67%). LCMS m/z 524.0 (M-tBu), 602.0 (M+Na), analHPLC >98% in purity. ¹H NMR (400 MHz; acetone-d6) δ7.77 (t, J=8.0 Hz,1H); 7.60 (m, 2H); 7.38 (m, 2H); 7.11 (m, 1H); 7.00 (m, 1H); 6.81 (s,1H); 5.35 (s, 2H); 3.80 (s, 3H); 2.70-3.30 (m, 3H); 2.40-2.60 (m, 2H);1.48 (s, 9H).

2-(1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)aceticacid was obtained from tert-butyl2-(1-(2,4-difluorobenzyl)-6-(3-fluoro-4-(trifluoromethyl)phenyl)-7-methoxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetateby the hydrolysis procedure described above with1,4-dioxane/hydrochloric acid.

EXAMPLE 13

A. Preparation of7-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one

To a solution of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (3.456 g, 21.18mmol) in anhydrous N,N-dimethylformamide (25 mL) was added potassiumcarbonate (4.146 g, 30.00 mmol), then and trifluoromethanesulfonylchloride (5.000 g, 29.67 mmol) in N,N-dimethylformamide (5 mL) dropwise.The reaction mixture was stirred at room temperature for 24 hours, and asecond portion of potassium carbonate (4.146 g, 30.00 mmol) andtrifluoromethanesulfonyl chloride (5.000 g, 29.67 mmol) inN,N-dimethylformamide (5 was added slowly, and stirred for 16 hours.Evaporation of the solvent under reduced pressure gave a crude mixtureto which a mixture of 15% ethyl acetate in n-hexane (20 mL) and water(50 mL) was added. Diethyl ether (5 mL) was added and the mixturesonicated, filtered, and the solid thus obtained was washed with 3Maqueous potassium carbonate (100 mL), water (200 mL), n-hexane (100 mL),15% ethyl acetate in n-hexane (30 mL), and dried to afford2-oxo-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate as ayellow solid (4.311 g, 14.60 mmol, 69%). LCMS mz 295.9 (M+H), 317.9(M+Na), anal HPLC >90% in purity, ¹H NMR (400 MHz; CDCl₃) δ8.17 (bs,1H); 7.23 (d, J=8.2 Hz, 1H); 6.90 (dd, J=8.2 and 2.3 Hz, 1H); 6.71 (d,J=2.3 Hz, 1H); 3.00 (m, 2H); 2.67 (m, 2H).

2-oxo-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate was thenconverted to7-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one, reactingwith 3-(trifluoromethyl)phenylboronic acid and following the proceduredescribed above in Example 1A above (204 mg, 0.70 mmol, 70%). LCMS mz292.0 (M+H), 314.0 (M+Na), anal HPLC >99% in purity, ¹H NMR (400 MHz;CDCl₃) δ7.78 (s, 1H); 7.72 (d, J=7.1 Hz, 1H); 7.50-7.64 (m, 2H); 7.49(bs, 1H); 7.15-7.35 (m, 2H); 6.92 (d, J=1.5 Hz, 1H); 3.03 (m, 2H); 2.69(m, 2H).

B. Preparation of tert-butyl2-(2-oxo-7-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate

7-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one was thenconverted to tert-butyl2-(2-oxo-7-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetateby reaction with tert-butyl 2-bromoacetate, following the proceduresdescribed above in Example 2B. (72 mg, 0.18 mmol, 89%). LCMS mz 350.0(M+H), 372.0 (M+Na), anal HPLC >96% in purity, ¹H NMR (400 MHz;acetone-d6) δ7.96 (s, 2H); 7.71 (s, 2H); 7.38 (s, 2H); 7.33 (s, 1H);4.84 (s, 2H); 3.03 (m, 2H); 2.67 (m, 2H).

C. Preparation of2-(2-oxo-7-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)aceticacid

tert-butyl2-(2-oxo-7-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetatewas then converted to2-(2-oxo-7-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)aceticacid using the procedure described above in Example 2C. (61 mg, 0.17mmol, 84%). LCMS mz 364.0 (M+H), 386.0 (M+Na), anal HPLC ˜100% inpurity, ¹H NMR (400 MHz; acetone-d6) δ8.00 (s, 2H); 7.71 (s, 2H); 7.57(s, 1H); 7.37 (s, 2H); 4.34 (t, J=7.6 Hz, 2H); 2.98 (m, 2H); 2.72 (m,2H); 2.61 (m, 2H).

Preparation of other Compounds of Formula (I) in which R⁴ is in the7-Position

Similarly, following the procedure described in Example 13A, 13B, and 13C above, but optionally replacing 3-(trifluoromethyl)phenylboronic acidwith other optionally substituted aryl boronic acids, the followingcompounds of Formula I were prepared:

-   -   7-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one;    -   7-(4-phenoxyphenyl)-3,4-dihydroquinolin-2(1H)-one;    -   7-(2,4,6-trifluorophenyl)-3,4-dihydroquinolin-2(1H)-one.

EXAMPLE 14

To a Biotage microwave vial was charged6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one (48 mg, 0.16mmol) and acetic anhydride-D6 (216 mg, 2.00 mmol). The reaction vial wassealed and subjected to microwave irradiation at 180° C. for 40 minutes.The mixture was cooled, transferred to a 25-mL flask, washed withmethylene chloride (5 mL), concentrated under reduced pressure,re-dissolved in methylene chloride (20 mL), transferred to a separationfunnel, washed with 1N sodium carbonate (10 mL), brine (10 mL), driedover magnesium sulfate, and the solvent removed under reduced pressure.The crude product was purified by preparative HPLC with a gradientacetonitrile/water (5-98%) to afford1-trideuteroacetyl-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one(50 mg, 0.15 mmol, 93%). LCMS mz 338.1 (M+H), 359.1 (M+Na), analHPLC >94% in purity.

EXAMPLE 15

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0The above ingredients are mixed and filled into hard gelatin capsules.

EXAMPLE 16

A tablet Formula (I)s prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0The components are blended and compressed to form tablets.

EXAMPLE 17

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

EXAMPLE 18

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Quantity Ingredient (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone  4.0 mg (as 10%solution in sterile water) Sodium carboxymethyl starch  4.5 mg Magnesiumstearate  0.5 mg Talc  1.0 mg Total  120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

EXAMPLE 19

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient   25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

EXAMPLE 20

Suspensions, each containing 50 mg of active ingredient per 5.0 mL doseare made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum  4.0 mg Sodiumcarboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mgSucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to  5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve, and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor, and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

EXAMPLE 21

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

EXAMPLE 22

An injectable preparation is prepared having the following composition:

Ingredients Amount Active ingredient 2.0 mg/ml Mannitol, USP 50 mg/mlGluconic acid, USP q.s. (pH 5-6) water (distilled, sterile) q.s. to 1.0ml Nitrogen Gas, NF q.s.

EXAMPLE 23

A topical preparation is prepared having the following composition:

Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients, and water thenadded q.s. 100 g.

EXAMPLE 24

Sustained Release Composition

Ingredient Weight Range % Active ingredient 50-95 Microcrystallinecellulose (filler)  1-35 Methacrylic acid copolymer  1-35 Sodiumhydroxide 0.1-1.0 Hydroxypropyl methylcellulose 0.5-5.0 Magnesiumstearate 0.5-5.0

The sustained release formulations of this invention are prepared asfollows: compound and pH-dependent binder and any optional excipientsare intimately mixed (dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate), andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent,for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Röhm.Pharma), and the like. These film-forming agents may optionally containcolorants, plasticizers, and other supplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg, and900-1100 mg.

In order to influence the dissolution rate, the time during which thecompound containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e. the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

EXAMPLE 25

Activity testing is conducted in the Examples below using methodsdescribed herein and those well known in the art.

Sodium Current Screening Assays:

The late sodium current (Late INa) and peak sodium current (Peak INa)assays were performed on an automated electrophysiology platform,PatchXpress 7000A (MDS Analytical Technologies, Sunnyvale, Calif.),which uses the whole cell patch clamp technique to measure currentsthrough the cell membrane of up to 16 cells at a time. The assay used anHEK293 (human embryonic kidney) cell line heterologously expressing thewild-type human cardiac sodium channel, hNa_(v)1.5, purchased fromMillipore (Billerica, Mass.). No beta subunits were coexpressed with theNa channel alpha subunit. Cells were maintained with standard tissueculture procedures and stable channel expression was maintained with 400μg/ml Geneticin in the culture medium. Cells isolated for use onPatchXpress were incubated for 5 minutes in Versene 1× and then for 2minutes in 0.0125% Trypsin-EDTA (both at 37° C.) to ensure that 80-90%of the cells are single and not part of a cell cluster. Experiments werecarried out at 24-27° C.

For both the Late Na and Peak INa assays, series resistance compensationwas set to 50% and whole-cell compensation was performed automatically.Currents were low-pass filtered at 10 kHz and digitized at 31.25 kHz.Currents through open sodium channels were automatically recorded andstored in the DataXpress2 database (MDS Analytical Technologies,Sunnyvale, Calif.). Analysis was performed using DataXpress2 analysissoftware and data are compiled in Excel.

Compound stocks were routinely made in glass vials to 10 mM in dimethylsulfoxide (DMSO). In some cases, when compounds were not soluble inDMSO, they were made in 100% ethanol. Stocks were sonicated asnecessary. The extracellular solution for screening Late INa wascomposed of: 140 mM NaCl, 4 mM KCl, 1.8 mM CaCl₂, 0.75 mM MgCl₂, and 5mM HEPES with pH adjusted to 7.4 using NaOH. The extracellular solutionfor screening Peak INa was composed of: 20 mM NaCl, 120 mM N-methyl-Dglucamine, 4 mM KCl, 1.8 mM CaCl₂, 0.75 mM MgCl₂, and 5 mM HEPES with pHadjusted to 7.4 using HCl. The intracellular solution used to perfusethe inside of the cells for both the Late Na and Peak INa assayscontains: 120 mM CsF, 20 mM CsCl, 5 mM EGTA, 5 mM HEPES and pH adjustedto 7.4 with CsOH. Compounds were diluted in extracellular solution to 10μM in glass vials and then transferred to glass well plates beforerobotic addition to the cells. The 0Na extracellular solution used atthe end of each experiment for the Late INa and Peak INa assays tomeasure baseline current contained: 140 mM N-methyl-D-glucamine; 4 mMKCl; 1.8 mM CaCl₂; 0.75 mM MgCl₂; 5 mM HEPES and pH was adjusted to 7.4with HCl.

Late INa Screening Assay:

For the Late Na assay, sodium channels were activated every 10 seconds(0.1 Hz) by depolarizing the cell membrane to −20 mV for 250milliseconds (ms) from a holding potential of −120 mV. In response to a−20 mV voltage step, typical Na_(v)1.5 sodium currents activated rapidlyto a peak negative current and then inactivated nearly completely within3-4 ms.

All compounds were tested to determine their activity in blocking thelate sodium current. Late Na current is generated by adding 10 μMTefluthrin (pyrethroid) to the extracellular solution while recording Nacurrents. For some experiments, 50 nM ATX II (sea anemone toxin),another late INa activator, was used to generate the late component.Both activators generate late components that are large enough thatblock of the late component by compounds can be measured easily. For thepurposes of the screening, late INa is defined as the mean currentbetween 225 ms and 250 ms after stepping to −20 mV to activate Nachannels. After establishing the whole cell recording configuration,late INa activators were added to each well 4 times over a 16-17 minuteperiod so that the late component of the Na current reached a stablevalue. Compounds were then added (typically at 10 μM), in the presenceof late INa activator, with 3 additions over the course of 7 or 8minutes. Measurements were made typically at the end of exposure to thethird compound addition. Measurements were made at the end of exposureto the third compound addition and values were normalized to the currentlevel when all Na⁺ was removed from the extracellular solution after twoadditions of 0Na-ECF. Results were reported as percent block of late INa

Peak INa Screening Assay:

Compounds were also evaluated for their effect in several other assays,including their effect on Peak INa. After screening compounds againstlate Na, selected compounds were evaluated for their effect in severalother assays, including their effect on peak INa. One goal of thisprogram is to avoid significant block of peak INa. Since the peak INa inour cells can be very large, introducing artifacts in the recording, theconcentration of Na⁺ in the bath is reduced to 20 mM and a nonpermeantcation is added to compensate for the Na⁺ that was removed to maintainthe osmolarity and ionic strength of the solution (see solution detailsabove). All measurements were normalized to the current level when allNa⁺ is removed from the extracellular solution, after two additions of0Na-ECF.

In some cases we measured the effect of compound on peak INa using datafrom the late INa assay. But often peak currents were too large to makethis possible, requiring that we perform a separate assay to evaluatethe effect on peak INa. For the original peak INa assay, we activatedthe channel every 10 seconds by depolarizing the cell membrane to −20 mVfor 250 ms from a holding potential of −120 mV. After establishing thewhole cell recording configuration, the recorded currents were allowedto stabilize for 6-7 minutes. Compound was added at 10 μM with threeadditions over an 8-9 minute period. Analysis of peak INa generallyrequired correction for rundown before determining the % block of peakcurrent by the tested compound.

A new Peak INa screening assay was developed to allow assessment of theeffect of compounds on peak INa at both low and high stimulationfrequencies. The goal was to find compounds that are highly selectivefor block of late INa but do not block peak INa. A low stimulationfrequency of 0.1 Hz was used to determine the effect of compound whenthe channel spends most of the time in the resting (closed) state andprovides information about Tonic Block (TB). A higher stimulationfrequency (3 Hz) was used to measure block of the channel when it spentmore time in the activated and inactivated states, and provided ameasure of Use-Dependent Block (UDB). The −100 mV holding potential andthe 3 Hz stimulation frequency were chosen so that our benchmarkcompound would have a small but detectable effect under experimentalconditions, allowing for direct comparison of new compounds with thebenchmark.

For the new peak INa assay, Na⁺ channels were activated by depolarizingthe cell membrane to 0 mV for 20 ms from a holding potential of −100 mV.After establishing the whole cell recording configuration, channels werestimulated to open with low frequency stimulation (0.1 Hz) for 7 minutesso that we could monitor the recording and assess the extent to whichthe recording had stabilized. After this stabilization period thestimulation frequency was increased to 3 Hz for 2 minutes, and thenreturned to 0.1 Hz. Since 3 Hz stimulation caused a small decrease inthe peak current even in the absence of compound, we used this internalcontrol for each cell, when no compound was present, to correct theresults from 3 Hz stimulation when compound was present. Following 3 Hzstimulation under control conditions, the cell was allowed to recoverfor 200 seconds before compound was added. Compound (10 μM) was added 3times at 60 second intervals, while stimulating the channels to open at0.1 Hz to monitor the progression of block. After the 3^(rd) compoundaddition, a 320 second wait period was imposed to allow forequilibration before the second period of 3 Hz stimulation begins. TBwas measured before the second period of 3 Hz stimulation. Both TB andUDB were analyzed by incorporating rundown correction for the peak INaand UDB was calculated by compensating for the small use-dependenteffect of the stimulation protocol on peak INa in the absence ofcompound.

hERG Screening Assay:

Compounds were screened to test their activity in blocking the hERGpotassium channel. The hERG channel was heterologously expressed in aCHO (Chinese Hamster Ovary) cell line. Cells were maintained withstandard tissue culture procedures and stable channel expression wasmaintained with 500 μg/ml G418 in the culture medium. Cells wereharvested for testing on the PatchXpress automated patch clamp withAccumax (Innovative Cell Technologies, San Diego, Calif.) to isolatesingle cells.

The following solutions were used for electrophysiological recordings.The external solution contained: 2 mM CaCl₂; 2 mM MgCl₂; 4 mM KCl; 150mM NaCl; 10 mM Glucose; 10 mM HEPES (pH 7.4 with 1M NaOH, osmolarity).The internal solution contained: 140 mM KCl, 10 mM MgCl₂, 6 mM EGTA, 5mM HEPES, 5 mM ATP (pH adjusted to 7.25 with KOH).

hERG channels are activated when the voltage is stepped to +20 mV fromthe −80 mV holding potential. During a 5 second step at +20 mV, thechannels activated and then largely inactivated, so the currents wererelatively small. Upon returning to −50 mV from +20 mV, hERG currentstransiently became much larger as inactivation was rapidly removed andthen the channel closed. The first step to −50 mV for 300 ms was used asa baseline for measuring the peak amplitude during the step to −50 mVafter channel activation. The peak current at −50 mV was measured bothunder control conditions and after addition of compound.

All compounds were prepared as 10 mM DMSO stocks in glass vials. Stocksolutions were mixed by vigorous vortexing and sonication for about 2minutes at room temperature. For testing, compounds were diluted inglass vials using an intermediate dilution step in pure DMSO and thenfurther diluted to working concentrations in external solution.Dilutions were prepared no longer than 20 minutes before use.

After achieving the whole-cell configuration, cells were monitored for90 seconds to assess stability and washed with external solution for 66seconds. The voltage protocol described above was then applied to thecells every 12 seconds and throughout the whole procedure. Only cellswith stable recording parameters and meeting specified health criteriawere allowed to enter the compound addition procedure.

External solution containing 0.1% DMSO (vehicle) was applied to thecells first to establish the control peak current amplitude. Afterallowing the current to stabilize for 3 to 5 minutes, 1 μM and then 10μM test compounds were applied. Each compound concentration was added 4times and cells were kept in test solution until the effect of thecompound reached steady state or for a maximum of 12 minutes. Afteraddition of test compound, a positive control (1 μM Cisapride) wasadded—it must block >95% of the current for the experiment to beconsidered valid. Washout in the external solution compartment wasperformed until the recovery of the current reached steady state. Datawere analyzed using DataXpress, Clampfit (Molecular Devices, Inc.,Sunnyvale) and Origin 7 (Originlab Corp.)

L-type Calcium Channel Activity Well-Plate Assay:

Cell Culture: IMR-32 (human neuroblastoma) cells were obtained from TheAmerican Type Culture Collection. The cells were maintained in MEMsupplemented with 10% fetal bovine serum, 2 mM of L-glutamine, 100 IU/mlof penicillin, 50 μg/ml of streptomycin, 1% of sodium pyruvate, 1% ofsodium bicarbonate and 1% of non-essential amino acid. The cells werecultured at 37° C. in a humidified 5% CO₂/95% air incubator. Culturemedium was changed every two days and cells were recultivated when theyreached 70-80% confluent.

Assay: IMR-32 cells were seeded on a Microtest 96-well Assay Plate (BDFALCON™) at a density of 200,000 cells/well in 200 μl culture medium forovernight. The culture medium was removed, and replaced by 120 μl Ca-4dye (MDS Analytical Technologies, Sunnyvale, Calif.) in HBSS (1× Hank'sBalanced Salt solution plus 20 mM HEPES, pH 7.4) containing 2 mMprobenecid. Cells were then incubated for 1 hour at 37° in incubator.Testing compounds were diluted from 5 μM-50 μM in HBSS, and 40 μl wereadded in cells before assay. L-type calcium channel activities (Max-Min)were measured after addition of 40 μl of 1 μM (−)Bay K 8644 plus 50 mMKCl (final concentration) using FlexStation (Molecular Devices)immediately after addition of testing compounds. The inhibition ofL-type calcium channel activity by compounds was then calculated.

Compounds were tested and found to be effective using the describedassay methods at a concentration of 1 μM and 10 μM in the late INa andPeak INa assays, and at 1 μM and 10 μM for the hERG and L-type calciumchannel assays. The assay results demonstrated that the compounds testedshowed activity as modulators of late sodium current, for example byinhibiting (or reducing) the late sodium current.

Compounds were tested using the described assay methods. Data wasobtained obtained by testing the listed compounds at 10 μM and 1 μMconcentrations in the late INa assay, and at 1 μM and 10 μM for the hERGand L-type calcium channel assays. Data are shown in Table 1 below forthose compounds that inhibit Late Ina by at least 10% at the 10 μMconcentration.

TABLE 1 Assay results hERG Patch Late INa Late INa Clamp % blk % blkhERG hERG Cmpd (10 μM test (1 μM test % blk % blk No. cmpd) cmpd) 1 μm10 μm 1 74 10 19 2 16 3 29 4 48 10 16 5 30 6 23 7 52 8 22 21 65 11 36 962 10 66 40 11 54 12 27 13 70 22 67 14 29 10 28 23 33 15 36 13 59 16 2424 74 44 44 21 10 10 25 20 26 32 60 25 10 10 26 20 10 10 27 52 12 47 2818 88 40 29 69 11 97 30 86 47.9 89 42 24 67 31 26 32 27 33 77 38.1 37 1990 22 49 60 10 42 34 60 13 37 50 76 51 14 53 73 35 69 89 48 16 72 44 4845 64 38 53 39 60 12 96 40 64 66 27 67 74 68 23 69 16 10 10 70 17 10 1041 12 54 13 55 14 56 14 58 13 10 10 77 72 78 34 79 12 80 17 81 30 105 4042 19 59 10 86 13 87 20 19 31 74 20 91 31 82 54The assay results shown in the above Table 1 establish that compoundstested showed activity as modulators of late sodium current, for exampleby inhibiting (or reducing) the late sodium current.

In some embodiments the effects of a compound of Formula (I) arespecific for the late sodium current and show little or no activity withrespect to one or more other ion channels. Thus, in some embodiments, acompound having an activity of reducing late sodium current will alsoexhibit little or no activity with regard to the peak sodium current. Inparticular embodiments, a compound having an activity of reducing latesodium current will also exhibit little or no activity with regard tothe hERG potassium channel. In some embodiments, a compound having anactivity of reducing late sodium current will also exhibit little or noactivity with regard to the L-type calcium channel. For example, a givencompound may provide a 30% (or greater, e.g. more than 40%, more than50%, more than 60%, more than 70%, more than 80%) reduction in latesodium current in the assay described herein, and the same compound mayexhibit little or no activity for one or more of the peak sodiumcurrent, the hERG potassium channel, and the L-type calcium channel. Inthis regard, a compound having “little” effect will typically show lessthen a 30% reduction (e.g. less than a 20% reduction, less than a 15%reduction, less than a 10% reduction) in the given activity (e.g. PeakINa, hERG, L-type calcium), when measured using the assay describedherein. In this regard, “no” effect means that any activity measuredwill differ from the control by less than the standard error of themeasurement. The assays conducted to measure activities in this regardshould be performed as described above, with the compound at aconcentration of 10 μM (or at the upper limit of solubility, if less).

L-type Ca2+ Channel Assay—ChanTest

Selected compounds were screened for block of the cardiac L-type Ca²⁺channel (hCav1.2, encoded by the human CACNA1C gene and coexpressed withthe beta 2 subunit, encoded by the human CACNB2 gene, and alpha2delta1,encoded by the CACNA2D1 gene). The Ca²⁺ channel was heterologouslyexpressed in a CHO (Chinese Hamster Ovary) cell line. Cells weremaintained following standard tissue culture procedures and stablechannel expression was maintained with appropriate selection antibioticsin the culture medium. Cells were harvested for testing on thePatchXpress automated patch clamp (Model 7000A, Molecular Devices,Sunnyvale, Calif.) by washing twice with Hank's Balanced Salt Solution,treating the cells with trypsin, and re-suspending cells in culturemedium (4-6×10⁶ cells in 20 mL). Cells in suspension were allowed torecover for 10 minutes in a tissue culture incubator set at 37° C. in ahumidified 95% air, 5% CO₂ atmosphere.

The following solutions were used for electrophysiological recordings.The external solution contains (mM): 137 NaCl, 4 KCl, 1.8 CaCl₂, 1MgCl₂, 10 Glucose, 10 HEPES (pH 7.4 with NaOH). The internal solutioncontains (mM): 130 Cs Aspartate, 5 MgCl₂, 5 EGTA, 4 ATP, 0.1 GTP, 10HEPES, (pH adjusted to 7.2 with N-methyl-D-glucamine).

Vehicle was applied to naïve cells (n≧2, where n=the number cells), fora 5-10 minute exposure interval. Each solution exchange was performed inquadruplicate. At the end of each experiment, a saturating concentrationof nifedipine (10 μM) was added to block hCav1.2 current. Leak currentwas digitally subtracted from the total membrane current record.

Test compound stock solutions were prepared by addition of dimethylsulfoxide (DMSO) and stored frozen. Each test compound DMSO stock wassonicated (Model 2510/5510, Branson Ultrasonics, Danbury, Conn.), atambient room temperature for at least 20 minutes to facilitatedissolution. Test compound concentrations were prepared fresh daily bydiluting stock solutions into the standard extracellular physiologicalsaline solution (see above). The maximum percent of DMSO added withcompound was 0.1%. All test compound and control solutions were placedin a glass-lined 96-well compound plate before loading on PatchXpress.

One or two concentrations (1, 10 μM) of each test compound was appliedat five (5) minute intervals via disposable polyethylene micropipettetips to naïve cells (n 2, where n=the number cells/concentration). Eachtest compound concentration was added to the cell in quadruplicate.Total duration of exposure to each test compound concentration was 5minutes.

Onset and steady state block of hCav1.2 channels was measured using astimulus voltage pattern consisting of a depolarizing test pulse(duration, 200 ms; amplitude, 10 mV) at 10 s intervals from a −80 mVholding potential. Peak current was measured during a step to 10 mV.

In particular embodiments, a compound will exhibit a high selectivityfor the late sodium current modulatory activity as compared to theactivity in one or more other ion channels. The selectivity of acompound may be determined by determining the percentage reduction inlate sodium current due to the compound, as measured by the assaydescribed above. The percentage reduction in one other ion channelactivity, such as the hERG potassium channel or L-type calcium channel,due to the compound is determined as described above. The selectivity isdetermined by taking the ratio of (percentage reduction in late sodiumcurrent) to (percentage reduction in one other ion channel activity).The assays conducted to measure activities in this regard should beperformed as described above, with the compound at a concentration of 10μM (or at the upper limit of solubility, if less). In particularembodiments, the selectivity of a compound of the invention will be atleast 5:1, e.g. at least 6:1, at least 7:1, at least 8:1, at least 9:1,at least 10:1, at least 12:1, at least 15:1, at least 20:1, or at least25:1, when comparing the percentage reduction in late sodium currentversus percentage reduction of one of the peak sodium current, the hERGpotassium channel current, or the L-type calcium channel.

What is claimed is:
 1. A compound selected from the group consisting of:2-{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetamide;2-[6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1 (2H)-yl]acetamide;2-{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetamide;2-{6-[4-chloro-3-(trifluoromethyl)phenyl]-2-oxo-3,4-dihydroquinolin-1(2H)-yl}acetamide;tert-butyl2-(6-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate;tert-butyl[6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;tert-butyl[6-(4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;tert-butyl {2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate; tert-butyl{6-[4-chloro-3-(trifluoromethyl)phenyl]-2-oxo-3,4-dihydroquinolin-1(2H)-yl}acetate;ethyl{2-oxo-6-[3-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;tert-butyl[6-(3-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;tert-butyl{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;ethyl[6-(2,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;tert-butyl[6-(4-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;ethyl[6-(3,4-difluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetate;{2-oxo-6-[3-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}aceticacid; [6-(4-chlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]aceticacid; {2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid;2-(6-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)aceticacid; ethyl{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;[6-(4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid;[6-(3-chloro-4-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]aceticacid; sodium {2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;[6-(3,4-dichlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid;{2-oxo-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetic acid;[6-(4-chloro-3-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]aceticacid; ethyl{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetate;[6-(3-fluorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid;tert-butyl2-(6-(3,4-dichlorophenyl)-2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetate;andtert-butyl-2-(7-methoxy-2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)acetate; or a pharmaceutically acceptable salt thereof.
 2. Acompound selected from the group consisting of:7-methoxy-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;8-bromo-6-(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one;6,8-bis(4-chlorophenyl)-7-methoxy-3,4-dihydroquinolin-2(1H)-one;[6,8-bis(4-chlorophenyl)-7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl]aceticacid; 6-(3-fluorophenyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one;6-(2,4-difluorophenyl)-1-(2-methoxyethyl)-3,4-dihydroquinolin-2(1H)-one;1-(2-hydroxypropyl)-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;1-(2-hydroxyethyl)-6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;6-(3,4-difluorophenyl)-1-(2-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one;1-(2-hydroxyethyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;6-(2,4-difluorophenyl)-1-(2-hydroxyethyl)-3,4-dihydroquinolin-2(1H)-one;6-(2,4-difluorophenyl)-1-(2,2,2-trifluoroethyl)-3,4-dihydroquinolin-2(1H)-one;{2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-1(2H)-yl}acetonitrile;6-(2,4-difluorophenyl)-1-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3,4-dihydroquinolin-2(1H)-one;6-[3-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;6-[4-chloro-3-(trifluoromethyl)phenyl]-3,4-dihydroquinolin-2(1H)-one;6-[4-(trifluoromethoxy)phenyl]-3,4-dihydroquinolin-2(1H)-one;6-(2,4-difluorophenyl)-3,4-dihydroquinolin-2(1H)-one;6-(2-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one;6-(4-fluorophenyl)-3,4-dihydroquinolin-2(1H)-one;2-fluoro-5-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile;3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzamide;6-(3-acetylphenyl)-3,4-dihydroquinolin-2(1H)-one;4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzamide;3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)benzonitrile; and6-[3-(morpholin-4-ylcarbonyl)phenyl]-3,4-dihydroquinolin-2(1H)-one; or apharmaceutically acceptable salt thereof.
 3. A method of treating adisease state in a mammal that is alleviable by treatment with an agentcapable of reducing late sodium current, wherein the disease state is acardiovascular disease selected from one or more of atrial andventricular arrhythmias, heart failure, congestive heart failure,diastolic heart failure, systolic heart failure, acute heart failure,Prinzmetal's (variant) angina, stable and unstable angina, exerciseinduced angina, ischemia, recurrent ischemia, reperfusion injury,myocardial infarction, acute coronary syndrome, peripheral arterialdisease, or intermittent claudication, comprising administering to amammal in need thereof a therapeutically effective dose of a compound ofclaim
 1. 4. A method of treating a disease state in a mammal that isalleviable by treatment with an agent capable of reducing late sodiumcurrent, wherein the disease state is a cardiovascular disease selectedfrom one or more of atrial and ventricular arrhythmias, heart failure,congestive heart failure, diastolic heart failure, systolic heartfailure, acute heart failure, Prinzmetal's (variant) angina, stable andunstable angina, exercise induced angina, ischemia, recurrent ischemia,reperfusion injury, myocardial infarction, acute coronary syndrome,peripheral arterial disease, or intermittent claudication, comprisingadministering to a mammal in need thereof a therapeutically effectivedose of a compound of claim
 2. 5. The method of claim 3, wherein thedisease state is diabetes or diabetic peripheral neuropathy.
 6. Themethod of claim 4, wherein the disease state is diabetes or diabeticperipheral neuropathy.
 7. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a therapeutically effectiveamount of a compound of claim
 1. 8. A pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and a therapeuticallyeffective amount of a compound of claim 2.